1,1,1,2,3,3,3-heptafluoropropane

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: Published in peer reviewed literature, adequate for assessment

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1996

Materials and methods

Objective of study:

other: biotransformation

Principles of method if other than guideline:

Investigation of the biotransformation of the test substance in vivo in rats and in rat and human liver microsomes.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

1,1,1,2,3,3,3-heptafluoropropane

EC Number:

207-079-2

EC Name:

1,1,1,2,3,3,3-heptafluoropropane

Cas Number:

431-89-0

Molecular formula:

C3HF7

IUPAC Name:

1,1,1,2,3,3,3-heptafluoropropane

Details on test material:

HFA-227, 99.99% pure, based on flame-ionization detector response, supplied from Hoechst (Frankfurt, Germany)

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

three male Sprague-Dawley rats were used

Administration / exposure

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Details on exposure:

Rats were individually exposed to 5000 ppm HFC 227ea in a closed, recirculating exposure chamber for 6 hr.

Duration and frequency of treatment / exposure:

Once for 6 hr

Doses / concentrations

Remarks:

Doses / Concentrations:
5000 ppm

No. of animals per sex per dose / concentration:

3 males

Control animals:

yes

Positive control reference chemical:

For the binding to human serum albumin experiment:
the acylating agent S-ethyltrifluoroacetate.

For the investigation regarding covalently binding to proteins in human liver microsomes:
a halothane metabolite

Details on study design:

See section 'Details on dosing and sampling'.

Details on dosing and sampling:

After the exposure, the animals were transferred to an all-glass metabolic cage and urine was collected for 24 hr. On collection, the urine was quickly frozen at -78 C and stored at -20 C. To record NMR spectra, the urine was filtered tyrough Millipore HV filters (45 microm) and 400 microl) of urine were mixed to 50 microl of D2O. To quantitate microsomal metabolism of HFC 227ea to inorganic fluoride, 5 ml of supernatant from the microsomal incubation or 5 ml of urine were combined with an equal volume of total ionic strength-adjustment buffer and analyzed with a fluoride-selective electrode and a reference electrode. Samples were constantly stirred and vlaues for the samples were taken after a 10-minutes eqquilibration period. Fluoride contents were quantitated by comparing the values obtained with those of standard curves.

Furthermore, microsomal incubations of HFC 227ea were performed with rat and human liver microsomes.

In addition, the potential of hexafluoroacetone trihydrate, the only metabolite of HFC 227ea, to bind covalently with nucleophilic sites was investigated.

Statistics:

Not specified

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

No data

Details on distribution in tissues:

No data

Details on excretion:

No data

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

19F-NMR identified hexafluoroacetone trihydrate in the urine of exposed rats. No significant increase of inorganic fluoride was observed in urinary excretion compared to untreated rats (0-48 hours after the end of the exposure). Because of the very low concentrations of hexafluoroacetone trihydrate present in the collected urine samples, the amount of this metabolite could not be quantified.
19F-NMR analysis of the supernatants of rat and human liver microsomes incubated with HFA-227ea showed consistent formation of fluoride only in liver microsomes from pyridine-pretreated rats and in two of the eight human liver samples. The rates of fluoride formation were very low and could not be quantified exactly (0.8 +/- 0.4 nmol/mg/20 min). The presence of traces of hexafluoroacetone trihydrate was indicated for the supernatants of incubations of HFA-227ea with liver microsomes from pyridine-retreated animals and for the two human liver samples catalyzing the formation of fluoride.

Any other information on results incl. tables

Because some aldehydes may covalently bind to proteins and the formation of fluorinated protein adducts has been implicated in immune-mediated hepatitis induced by halothane, the binding of hexafluoroacetone trihydrate to proteins was also investigated. Hexafluoroacetone trihydrate also gave only a very small resonance in fluorine NMR experiments when binding to human serum albumin was studied in comparison with the acylating agent S-ethyltrifluoroacetate. Moreover, no fluorine-containing products were formed by the reaction of hexafluoroacetone trihydrate with N^α-acetyl-L-Iysine, and hexafluoroacetone trihydrate was not metabolized to fluorine-containing metabolites or inorganic fluoride in rats. Comparative studies in human liver microsomes demonstrated that a halothane metabolite may covalently bind to proteins; in contrast, metabolism and covalent binding of HFA 227ea could not be demonstrated.

The data indicate that HFA-227 is biotransformed at very low rates to hexafluoroacetone trihydrate but irreversible binding of hexafluoroacetone trihydrate cannot be demonstrated, even with the application of very sensitive methods, and is considered unlikely, based on the combination of the results obtained.