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Description of key information

Key value for chemical safety assessment

Additional information

Only toxicokinetic studies with animals via the respiratory route are present in the available database.

 

Absorption

In rats, relative absorption after respiratory exposure is considerably more than 1% of the VDF available in a closed exposure system, but could not be quantified more exactly, based on the available data. The rate of absorption and distribution of VDF are relatively high, steady state blood levels of VDF are reached within 15 minutes after onset of respiratory exposure.

 

Distribution into tissues

In the rat, the rapid obtainment of steady state concentrations and the equally rapid decrease of blood concentrations after cessation of exposure suggest that VDF has limited solubility in tissues of varying lipid and aqueous content. VDF tissue/air partition coefficients were determined experimentally to be 0.07, 0.18, 0.8, 1.0, and 0.29 for water, blood, liver, fat, and muscle, respectively. In view of these data, bio-accumulation of VDF in the rat is unlikely.

 

Transfer into organs

No data are available, but accumulation in organs is unlikely in view of the results obtained on distribution into tissues.

 

Excretion

In rats, after cessation of exposure, blood levels of VDF decreased to 10% of steady-state levels within 1 hour. This indicates excretion is a rather rapid process. The quantitative importance of faecal and urinary excretion cannot be addressed based on the available data. However, judging by the rapid equilibration with ambient air, faecal and urinary excretion are probably of little quantitative significance.

 

Metabolism

In the rat, no metabolites of VDF were identified. After respiratory exposure, rats exhaled acetone (between 1.2 and 2.5 μmol/h/kg bw when exposed to 500 ppm VDF for 8 hours). However, whether it is a de facto metabolite of VDF or the result of inhibition of citric acid cycle enzyme(s) by a true VDF metabolite, e.g. fluoroacetate, is still undecided based on the available data.

 

Based on the scant information presented above and considerations regarding the chemical structure of VDF, the following metabolic reactions were putatively proposed:

- epoxidation of the ethylene double bond;

- rearrangement to the halogenated acetaldehyde or halogenated acyl halide;

- partial transformation of the latter to halogenated acetic acid.

 

Although, in the rat, respiratory uptake of VDF increases linearly with its concentration in air, metabolism may be saturated from a certain exposure concentration upward. However, different results were obtained with respect to the saturation point of the metabolism. Zwart (1985) calculated a saturation point of ca. 400 ± 200 ppm in air, while Filser et al. (1982) found it to be 100 ppm, in a different rat strain. Using the kinetic data of Filser et al. (1982) in a PBPK-model, which correctly predicted VDF blood concentrations, Medinsky et al. (1988) calculated a saturation point of 2000 ppm. As the PBPK-model correctly predicted VDF blood levels, providing some validation of the model and its underlying data, 2000 ppm seems to be the best estimate of the metabolic saturation point. Estimations of Vmax for metabolic elimination in the rat varied between 1.1 μM/h/kg bw and 3.2 μmol/h/kg bw. (As it is not clear from the SIDS summary of the OECD to which volume the unit expressed in μM is related, both units cannot be interconverted to facilitate comparison.)