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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1986
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is well conducted for its purpose. It gives some information regarding distribution of the test substance but due to the nature of the work (research), no guideline followed and only few tissues were examined.

Data source

Reference
Reference Type:
publication
Title:
Distribution of Halothane and the Metabolites Trifluoroacetic Acid and Bromide in the Conceptus after Halothane Inhalation by Pregnant Mice
Author:
Ghantous H et al.
Year:
1986
Bibliographic source:
Acta pharmacol. et toxicol. 59, 370-376
Report Date:
1986

Materials and methods

Objective of study:
distribution
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Trifluoroacetic acid (which is a metabolite of halothane) and halothane were tested in the study in parallel. Trifluoroacetic acid was administered to pregnant mice by intravenous injection and the plasma and amniotic fluid were collected for the analysis. In parallel halothane was administered to pregnant mice by inhalation route for 1 hour. Subsequently, the mice were killed and blood and amniotic fluid were collected for the analysis of distribution of halothane in fetuses and in body fluids.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
no

Test animals

Species:
mouse
Strain:
C57BL
Sex:
female

Administration / exposure

Route of administration:
other: Inhalation for Halothane, intravenously for TFA
Vehicle:
other: saline solution for TFA
Duration and frequency of treatment / exposure:
single dose (TFA)
single dose for 1 hour (halothane)
Doses / concentrations
Remarks:
Doses / Concentrations:
10 µmol (TFA)
No. of animals per sex per dose:
8 mice pregnant on day 18 of gestation
Control animals:
no

Results and discussion

Preliminary studies:
no
Main ADME results
Type:
other: Distribution and accumulation
Results:
Trifluoroacetic acid (TFA) was accumulated and retained in amniotic fluid after exposure of preganant mice with Halothane or after infusion in maternal blood with TFA.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
not applicable
Details on distribution in tissues:
The concentration of halothane in maternal plasma decreased rapidly. In the amniotic fluid the halothane never reached more than 20 % of maternal plasma levels. Trifluoroacetic acid (TFA), formed mainly by maternal metabolism of halothane, accumulated in foetus and amniotic fluid with time, and reached plateau levels in amniotic fluid between 4 and 24 hrs. TFA infused intravenously to the mother reached higher levels in amniotic fluid after long survival times than in maternal plasma.
Transfer into organsopen allclose all
Test no.:
#1
Transfer type:
blood/placenta barrier
Observation:
slight transfer
Remarks:
after inhalation exposure halothane appeared in the conceptus but 4 hours after the end of exposure the concentration of halothane in maternal blood and amniotic blood was very low or null.
Test no.:
#2
Transfer type:
blood/placenta barrier
Observation:
distinct transfer
Remarks:
TFA was accumulated and retained in amniotic fluid after inhalation exposure of pregnant mice with halothane or after infusion in maternal blood with TFA. TFA is mainly formed by maternal metabolism
Details on excretion:
not applicable

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
TFA is formed as a result of halothane metabolism (mainly maternal metabolism)

Applicant's summary and conclusion