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Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Type of information:
other: Expert Assessment
Adequacy of study:
supporting study
Study period:
November 2017
Reliability:
other: Assessment of available experimental data and literature review
Objective of study:
absorption
distribution
excretion
metabolism
GLP compliance:
no
Specific details on test material used for the study:
Not applicable
Details on absorption:
Based on the physical form of the substance, a gas under pressure, and physicochemical properties (Boiling point: ca 5.5 °C, and vapour pressure (1768 hPa)), the main relevant absorption route is pulmonary.
Details on distribution in tissues:
Following absorption, distribution of the substance is expected based on the relatively low molecular weight (162.03 g/mol). There is evidence of systemic distribution of the substance or its metabolites in the available acute inhalation toxicity, and several repeated dose toxicity studies (14-day and 28-day) available in the dataset which showed toxicological effects on various organs (especially liver and kidney) following single or repeated exposures.
Details on excretion:
There are no specific experimental data regarding the potential excretion of the substance or conjugated metabolites in the feces or in urine, however, there was a dose-related increase in urinary fluoride in both males and females rats treated for 28-day by inhalation, consistent with the excretion of metabolites in the urine (Bowden, 2003).
Metabolites identified:
not measured

Absorption:

Based on the physical form of the substance, a gas under pressure, and physicochemical properties (Boiling point: ca 5.5 °C, and vapour pressure (1768 hPa)), the main relevant absorption route is pulmonary.

The water solubility is relatively low (230.5 mg/L) and thus not favourable to dissolution and significant absorption along the respiratory tract, thus the gas is more likely to reach directly the deep lung and the gas exchange region. However given the very high vapour pressure, low water solubility and logKow values, a fraction of the gas may be re-exhaled without being absorbed.

Results of the acute inhalation study (Robinson, 1993) still showed absorption especially at high concentrations as all the animals exposed to 20 mg/L died rapidly within one hour after the 4-hour exposure, in addition to one female of this group which was found dead in the exposure chamber at the end of the exposure period.

In the absence of further information on the quantity absorbed, the default maximized absorption is set at 100% for the inhalation route.

There is no specific evidence of a potential absorption of the substance by the dermal route, but it can be considered unlikely based on the very high vapour pressure.

Distribution:

Following absorption, distribution of the substance is expected based on the relatively low molecular weight (162.03 g/mol). There is evidence of systemic distribution of the substance or its metabolites in the available acute inhalation toxicity, and several repeated dose toxicity studies (14-day and 28-day) available in the dataset which showed toxicological effects on various organs (especially liver and kidney) following single or repeated exposures.

Changes in various parameters included body weight gain, organ weights (more specifically, liver and/or kidney weights) and histopathological findings in the kidneys (Bowden, 2003, Theuns-van Vliet, 2017). Changes in the teeth/dentine composition with observation of blue strip pattern in Wistar rats treated for 28 days (part of the OECD421 study) were also signs of a systemic distribution of the substance or its fluorinated metabolites (Theuns-van Vliet, 2017).

There is no detailed information on the kinetics of distribution, however evidence of systemic distribution is shown by macroscopic findings on the liver (dark liver) in the animals treated at the high concentration for 4-hours and found dead within an hour post-exposure in the acute inhalation study.

Metabolisation:

The absorbed substance might undergo metabolisation. Information available on structurally-related substances (haloalkenes) tends to indicate conjugation might be a relevant pathway. In particular, the nephrotoxic effects observed in rodents with several haloalkene derivatives has been investigated and found to be linked to a glutathione-dependent bioactivation of the haloalkenes (Lock, 1988; Cassarett and Doull, 2007; Hayes, 2007). The proposed mechanism developed for some halogenated derivatives (e.g., hexachlorobutadiene, tetrafluoroethylene, hexafluoropropene) involves glutathione conjugation in the liver, excretion into the bile of the glutathione S-conjugates formed (typically as S-(1,1-difluoroalkyl)glutathione conjugates), followed by further metabolisation (in the bile duct or intestinal epithelial cells) by γ-glutamyl transferase and dipeptidases to form cysteine S-conjugates and/or N-acetylcysteine S-conjugates (mercapturic pathway). The cysteine S-conjugates can be reabsorbed from the Gut, and undergo enterohepatic circulation, or enter the systemic circulation and be translocated to the kidney where they are substrates for either (i) renal β-lyase (cytosolic or mitochondrial) to form reactive electrophilic intermediates (e.g., thiolates and subsequently thioacylfluorides) which can react with tissue nucleophiles and result in nephrotoxicity (Hayes, 2007; Dekant and Henschler, 1999), or (ii) acetylated to form the corresponding mercapturic acids excreted in the urine.

The extent of the nephrotoxic effects may thus depend on the metabolic balance (pathways may differ between compounds), the dose administered, species and sex. In addition, metabolic differences have been identified between chlorinated and fluoroalkenes and among fluoroalkenes, thus effects observed with hexachlorobutadiene or other fluoroalkenes may not be fully transposable to hexafluorobutadiene although nephrotoxicity is a common feature.

Renal β-lyase activity has been found to be lower in human kidney than in rat kidney, suggesting that this pathway is less prevalent in humans who thus may be less sensitive to nephrotoxic effects of cysteine S-conjugates compared to rats (Anders and Dekant, 1998; Dekant, 1999).

An in vitro preliminary study assessing glutathione conjugation reactions with hexafluorobutadiene in rat and human liver microsomes and cytosol showed a depletion of glutathione more predominantly in rat liver microsomes after treatment with HFBD. LC-MS spectra analysis was consistent with the formation of glutathione conjugates both by addition and substitution reactions.

This pathway is consistent with the specific renal toxicity observed in rats, as showed by the kidney weight increase, and cortical tubular basophilia observed especially at high concentration exposure (99 ppm, 14-day exposure). Differences in intensity and effects can be noted between rat strains tested in two different studies.

However, the formation of hyaline droplets in tubular cells reported in male rats following a 28-day treatment may be related to another pathway specific to male rats, involving accumulation of α-2u-globulin in the kidney and considered of no relevance to human.

Excretion:

There no specific experimental data regarding the potential excretion of the substance or conjugated metabolites in the feces or in urine, however, there was a dose-related increase in urinary fluoride in both males and females rats treated for 28-day by inhalation, consistent with the excretion of metabolites in the urine (Bowden, 2003).

Elimination of the glutathione conjugates usually occurs via the bile into the feces, or after bio-transformation to mercapturic acids, in the urine. The elimination through one or the other pathway may be dose-dependent.

The organ-specific toxicity to the kidneys in rats, as evidenced at least by the increased kidney weight in all the repeated dose toxicity studies, is consistent with elimination of the substance or its conjugates via urine. Similar results have been reported for other related fluorinated structures (Lock, 1988).

Conclusions:
The ADME properties of the substance have been assessed based on the information from the available experimental studies and physico-chemical properties. Preliminary in vitro experiments showed the formation of glutathione conjugates in rat liver microsomes, a first step in the metabolic pathway identified for other haloalkenes.
Results of the experimental toxicity studies in rats reported in this dataset provided evidence of absorption, distribution, metabolisation and excretion of the registered substance following exposure by inhalation. Published data on related fluoroalkenes provided also useful information on the potential metabolic pathways and proposed mechanisms involved in the nephrotoxicity, in particular possibly via beta-lyase metabolisation in the kidney.

Description of key information

The ADME properties of the substance have been assessed based on the information from the available experimental studies and physico-chemical properties. Published data on related fluoroalkenes can provide also useful information on the potential metabolic pathways involving conjugation to glutathione and proposed mechanisms involved in the nephrotoxicity, in particular possibly via beta-lyase metabolisation in the kidney.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - inhalation (%):
100

Additional information

An absoprtion rate of 100% is conservative as a large fraction of the inhaled substance is likely exhaled before systemic absorption.

Based on the low LogKow determined experimentally, the substance has a low bioaccumulation potential.