Tetradecafluorohexane

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

November 2019

Reliability:

other: Not relevant for an expert statement

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

toxicokinetics

Principles of method if other than guideline:

This theoretical assessment was prepared, taking all currently available relevant information into account, based on the REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance.

GLP compliance:

no

Remarks:

Not applicable

Conclusions:

5. TOXICOKINETIC ASSESSMENT

A substance can enter the body via de gastrointestinal tract, the lungs, and the skin1. Since different parameters are relevant for absorption via the different routes of exposure, the uptake via these three routes will be addressed individually.
After oral administration, a compound needs to be dissolved before it can be taken up from the gastrointestinal tract.1 Since the water solubility of Tetradecafluorohexane is very low (≤0.1 mg/L), the substance is expected to be poorly dissolved in gastrointestinal fluids,
therefore the availability for uptake is limited. Based on its moderate molecular weight (338), uptake via passive diffusion might occur, but might be too big for passage through aqueous pores or carriage across membranes with the bulk passage of water, also because its water solubility is low. Tetradecafluorohexane has a relatively high partition coefficient (log Pow ≥ 4.5), which is considered not favourable for passive diffusion, but the uptake via micellular solubilisation by bile salts can be expected to take place, enhancing the absorption. The substance does not have ionisable groups that could than can influence its absorption. For risk assessment purposes, oral absorption of Tetradecafluorohexane is set at 10%, based on its low water solubility, moderate molecular weight and high log Pow. The oral toxicity data do not provide reasons to deviate from the proposed oral absorption factor.2
Tetradecafluorohexane has low water solubility, so its dissolution in mucus lining in the respiratory tract may be limited. Moreover, Tetradecafluorohexane has a high partition coefficient (log Pow ≥ 4.5), which is considered not favourable for passive diffusion through biological membranes. However, Tetradecafluorohexane has a high vapour pressure (30.9 kPa at 20°C), which indicates that Tetradecafluorohexane is highly volatile (vapour pressure
>25 kPa) and exposure by inhalation is possible. Very lipophilic vapours (log Pow >4) have the ability to reach the deep lung, where absorption through gas exchange may occur.2 Tetradecafluorohexane is a liquid, which indicates that exposure via areosols is also possible. Aerosols can reach the tracheobronquial region of the respiratory tract. Taking in consideration all these factors together, it is concluded that for risk assessment purposes, as a worst case scenario, the inhalation absorption should be set at 100%.2
Tetradecafluorohexane is a liquid with very low water solubility, it will only dissolve to a very small extent into the surface moisture of the skin to allow uptake. The relatively high log Pow (>4) indicates the crossing of epidermal barriers will be limited. According to the criteria given in the REACH Guidance2, a default value of 100% dermal absorption has been established if the molecular weight is lower than 500 and log P between -1 and 4. The physical/chemical properties of Tetradecafluorohexane do not fully meet the criteria for full dermal absorption (MW 338; log Pow ≥4.5). As it is generally accepted that dermal absorption is not higher than oral absorption, for risk assessment purposes a dermal absorption of 10% will be considered as a more realistic worst case2. Tetradecafluorohexane is neither skin irritating nor corrosive, so enhanced uptake related to local effects need not to be considered.

Once absorbed, distribution of the substance throughout the body is expected to be limited based on its very low water solubility, relatively high log Pow and moderate molecular weight. Orally absorbed Tetradecafluorohexane may be metabolized in the gastrointestinal tract or the liver and excreted through bile and urine. As a very volatile substance, it may be excreted through exhaled air.3 Based on its relatively high partition coefficient (log Pow ≥ 4.5), Tetradecafluorohexane may accumulate in adipose tissue (intracellular concentration may be higher than the extracellular concentration). However, based on its very low water

solubility and high molecular weight, the overall bioaccumulation potential of Tetradecafluorohexane is expected to be low.

6. CONCLUSION
A toxicokinetic assessment was performed based on the available data of the substance. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 10% (oral), 100% (inhalation) and 10% (dermal) for risk assessment purposes. The bioaccumulation potential is expected to be low.

Executive summary:

A toxicokinetic assessment was performed based on the available data of the substance. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 10% (oral), 100% (inhalation) and 10% (dermal) for risk assessment purposes. The bioaccumulation potential is expected to be low.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Remarks:

Elimination of Perfluorohexane from AF0150 in Expired Air in Rats with Pharmacokinetic Evaluation of Perfluorohexane in Blood

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

In-life phase: December 14, 1994 - February 27, 1999; Report date: June 28, 1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Remarks:

Application 21191 for marketing authorization of a medicinal product, US FDA (succesfull application)

Objective of study:

toxicokinetics

GLP compliance:

yes

Radiolabelling:

no

Species:

rat

Strain:

CD-1

Remarks:

CD (SD)IGS BR

Details on species / strain selection:

The animais were 9-11 weeks old with body weights of 269-
315 g for males, and 10-17 weeks old with body weights of 345-376 g for feniales at initiation of treatment.

Sex:

male/female

Details on test animals or test system and environmental conditions:

Standard procedures were followed for housing, handling, feeding and care of the animais. The rats were acclimated for at least 1 week before initiation of treatment. Seven and 5 rats each sex were used for expired air PFH and blood PFH analyses, respectively.
7 + 5 rats/sex

Route of administration:

intravenous

Vehicle:

water

Details on exposure:

AF0150 Preparation and Administration: AF0150 (400 mg fill) was reconstituted with 10 ml SWFI to a final concentration of 40 mg/kg and used within 30 minutes. Animais received 20 mg/kg AF0150 through IV injection into a pre-inserted indwelling catheter in the tail vein. A single bolus injection was given to each animal. For the expired air evaluation, rats were sealed within a glass tube with the catheter exteriorized through a rubber seal. Dose was calculated based on pre-test body weight.
Observations: Mortality and clinical signs were observed twice daily. Expired air and blood samples were collected alter AF0150 administration as follows, and PFH in these samples was analyzed.

Duration and frequency of treatment / exposure:

UNique IV bolus

Dose / conc.:

20 mg/kg bw/day

Remarks:

unique bolus

No. of animals per sex per dose / concentration:

Seven and 5 rats each sex were used for expired air PFH and blood PFH analyses, respectively.

Control animals:

no

Positive control reference chemical:

Not relevant

Details on dosing and sampling:

Expired Air PFH Analysis: Expired air samples were collected from each of 7 rats/sex. The samples were drawn from the glass tube (where each individuai animal was retained) into the sample tubes (2/sex, Figure 1) or the gas bags (5/sex, Figure 2). Airflow was 300 ml/minute (based on a pilot study results) and went past the animal body and snout. With the gas bag sampling, 100% of the expired air was collected for 3 hours into 80-liter Tedlar bag. Samplesafter the 3-hour time point were directly collected onto adsorbent cartridges containing
PFH in the expired air samples was measured by For the tube sampling,
expired air samples were collected with the adsorbent trapping procedure in real time: for the first 5 minutes (1-minute interval), the second 5 minutes (2.5-minutes intervals), next 50 minutes (12.5-minute interval) up to 180 minutes (100% expired air) post-dosing. The animais were then returned to the chamber for additional sampling at 8, 24 and 48 hours after dosing.
Blood PFH Analysis: Eleven serial blood samples (0.25m1/sample) were taken from each of 5 rats/sex via a pre-inserted femoral vein catheter up to 24 hours post doing. Collection time-points were 0 (pre-dosing), immediately (within 1 minute), 2, 5, 15, 30, 45 minutes; 1, 4, 8 and 24 hours after dosing.
Dose Verification: Aliquots (0.25 ml) of reconstituted AF0150 were taken from each vial at immediately pre-dosing and post-dosing for each animal. PFH levels in the samples were
analyzed using The mean value of these two determinations was used for
calculation of total AF0150 dose (PFH, ug) and PFH recovery.

Type:

other: PFH Analysis in the Injected Dose

Results:

PFH Analysis in the Injected Dose: The the exact dose to the animais ranged from 18 to 45 ug PFH per animal in Expired Air Study group. In Blood PFH Study group, the exact animal dose was 33-44 ug PFH.

Type:

excretion

Results:

PFH Analysis in Expired Air: Gas bag sampling: approximately 94% within the first 3 hours, 98% at 6-11 hours and 103% at 24-28 hours. Tube sampling: PFH recoveries were 78% at the first 3 hours, 87% at 6-10 hours and 87% at 24-28 hours.

Type:

excretion

Results:

Blood PFH level decreased by 78±20.1% during the first 2 minutes following IV injection of AF0150 (20 mg/kg). PFH was not detectable in blood by 24 hours post dosing. The terminal half-life of PFH was 87.8 minutes for males and 88.8 minutes for females

Details on distribution in tissues:

The excretion kinetics of PFH from the expired air fitted a two-compartment model within the first 3 hours, as seen in Figure 3. The initial rapid elimination phase was from plasma, followed by a slow elimination phase contained distribution phase, which was most likely from adipose tissues. The haif-life values for the initial elimination phase and slow elimination phase were not provided.

Details on excretion:

1. Pharmacokinetics of AFOI 50 following single bolus IV injection at 20 mg/kg (26-fold PCD) in rat was measured based on PFH elimination from expired air and blood. About 90% of the administrated PFH was excreted from lungs within the first 3 hours post dosing and was almost completely eliminated within 48 hours. PFH in blood had the same profile as in expired air, with a two-compartment model. Blood PFH level decreased by 78% during the first 2 minutes post dosing, and was non-detectable by 24 hours.
2. The terminal elimination half-life of blood PFH was about 88 minutes. However, this was based on the pooled data from individual animais. Due to technical difficulties to accurately measure blood PFH level, as noted by the great variations in PFH values, the individual half¬life, as well as other PK parameters, need to be calculated and the range of half-life of PFH elimination should be provided.

Metabolites identified:

no

Remarks:

The perflexane was approximately totally recovered at the end of the study

Executive summary:

The major elimination route of PFH, one of AF0150 major components, was through expiratory air. At IV bolus dose of 20 mg/kg (26-fold) in rats, about 90% of PFH was excreted from expired air within 3 hours post dosing. PFH in blood decreased by 78% within the first 2 minutes post dosing, and became non-detectable by 24 hours. The terminal blood haif-life of PFH was 88 minutes. Kinetics profiles of PFH in both expired air and blood fitted into a two-compartment model. The following issues need to be further addressed

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1993

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

distribution

excretion

metabolism

Principles of method if other than guideline:

Rats were exposed to PFH by inhalation. Tissues and excretion were then anylised for presence of PFH or eventual metabolites.

GLP compliance:

no

Specific details on test material used for the study:

Details on test material available:
Brashear, W.T., Ketcha, M.M., Pollard, D.L., Godin, C.S., Leahy, H.F.. Lu, P.P.. Kinkead, E.R. and
Wolfe, R.E. (1992) Metabohte identification of halon replacement compounds. Report No. AL-TR1992-0078,
Wright-Patterson AFB, Dayton, OH.

Radiolabelling:

no

Species:

rat

Strain:

Fischer 344

Remarks:

and Sprague-Dawley

Sex:

not specified

Details on test animals or test system and environmental conditions:

Both Fischer 344 (F-344) and SpragueDawley
male rats, 6 to 8 weeks of age, were used.

Route of administration:

inhalation: gas

Vehicle:

unchanged (no vehicle)

Details on exposure:

Groups of eight were exposed by
nose-only inhalation to 1% (10.000 ppm) air atmosphere of the test chemical for 2 h.

Duration and frequency of treatment / exposure:

Unique exposure, 2h, continuous.

Dose / conc.:

10 000 ppm

Remarks:

1%

No. of animals per sex per dose / concentration:

8 animals per species, 1 dose
2 control

Control animals:

yes, concurrent no treatment

Positive control reference chemical:

Not relevant

Details on study design:

For the metabolism portion of this study, both Fischer 344 (F-344) and SpragueDawley
male rats, 6 to 8 weeks of age, were used. Groups of eight were exposed by
nose-only inhalation to 1% (10.000 ppm) air atmosphere of the test chemical for 2 h.
Details of the test chemicals have been described [l]. Two control rats were exposed
to air only. Following exposure, four test and one control rat were immediately
euthanatized via CO, inhalation, and samples from the following tissues were removed,
quick-frozen in liquid nitrogen, and stored at -20°C for analysis: blood, liver,
kidney, skin, muscle, testes, heart, lung, and fat. The remaining four test and one
control animals were placed into metabolism cages for 24 h and then sacrificed. In
this procedure, urine and feces were collected. During the collection, urine was kept
at 0°C and feces were kept below room temperature.
Approximately half-gram samples of blood or tissue were placed into vials for
headspace analysis of the volatile metabolites by gas chromatography (GC) with
electron capture detection (ECD) or by GC/mass spectrometry (MS) with subambient
cryofocusing. Details of the analytical procedures, including instrument conditions,
have been described [l]. For urine samples, 2-ml samples were centrifuged, the supernatant
decanted, and loo-@ aliquots were combined with TISAB II buffer. Fluoride
ion concentration was determined from a standard curve generated with control rat
urine. For the analysis of carboxylic acids and bromide, loo-@ samples of urine were
derivatized with dimethyl sulfate in headspace vials followed by GC/MS analysis.
Because of the low concentrations of bromide in these samples, GCYMS was done
using selected ion monitoring. Selected samples of urine, liver, and testes from rats exposed to HCFC-123 or PFH were examined by fluorine-19 nuclear magnetic resonance
spectrometry {19F-NMR). This technique detects volatile as well as nonvolatile
metabolites containing fluorine.

Type:

distribution

Results:

Perhuorohexane (PFH) was detected in all tissues sampled from both F-344 and Sprague-Dawley rats sacrificed immediately postexposure. At 24 h, PFH was detected in the fat only.

Type:

metabolism

Results:

No metabolites of PFH were detected. The metabolism of PFH, if any, remains to be elucidated.

Type:

excretion

Results:

One assumes that the disappearance of PFH following inhalation is entirely due to expiration.

Metabolites identified:

no

Details on metabolites:

No metabolites of PFH were detected. The metabolism of PFH, if
any, remains to be elucidated.

Executive summary:

Perhuorohexane (PFH) was detected in all tissues sampled from both F-344 and Sprague-Dawley rats sacrificed immediately postexposure. At 24 h, PFH was detected in the fat only. No metabolites of PFH were detected. The metabolism of PFH, if any, remains to be elucidated. One assumes that the disappearance of PFH following inhalation is entirely due to expiration. Toxicological investigations with PFH have been limited to acute and subchronic 43 general toxicity evaluations. Results to-date indicate minimal alterations in PFHexposed rats [19]. A noteworthy consideration for PFH and other perlluoro compounds regarding substitution for ozone-depleting halogenated hydrocarbons is their recalcitrance toward degradation which might, with time, have an environmental impact.

[19]Product Toxicity Summary Sheet on FLUORINERT Brand Electronic Liquid FC-72, 3M Center, September 9, 1990.

Reference 4

Endpoint:

basic toxicokinetics in vitro / ex vivo

Remarks:

Binding to albumin

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Remarks:

Assessed by FDA: New drug application of AF0150

Objective of study:

bioaccessibility (or bioavailability)

distribution

Principles of method if other than guideline:

Excess liquid perflexane was equilibrated with five différent aqueous solutions at 37°C. The aqueous solutions were as Follows: (1) distilled water, (2) phosphate buffered saline (PBS), (3) 1% Albumin, USP in PBS. (4) 5% Albumin, USP in PBS, and (5) 10% Albumin, USP in PBS.
The perflexane-aqueous mixtures were centrifurged and samples of the ciear aqueous phase were removed for analysis. Quadruplicate samples ware sealed into headspace vials and analyzed for perflexane.

GLP compliance:

yes

Radiolabelling:

no

Species:

other: In vitro binding to albumin. Origin of albumiun unknown.

Dose / conc.:

8 ppm

Remarks:

range - lower concentration

Dose / conc.:

13 ppm

Remarks:

range - upper concentration

Control animals:

other: Not relevant

Details on study design:

Excess liquid perflexane was equilibrated with five différent aqueous solutions at 37°C. The aqueous solutions were as Follows: (1) distilled water, (2) phosphate buffered saline (PBS), (3) 1% Albumin, USP in PBS. (4) 5% Albumin, USP in PBS, and (5) 10% Albumin, USP in PBS.
The perflexane-aqueous mixtures were centrifurged and samples of the ciear aqueous phase were removed for analysis. Quadruplicate samples ware sealed into headspace vials and analyzed for perflexane.

Type:

other: Binding to blood protein

Results:

The results suggest that the solubility of perflexan is very low, indicating a low affinity for protein binding

Conclusions:

The results suggest that the solubility of perflexan is very low, indicating a low affinity for protein binding

Executive summary:

The results suggest that the solubility of perflexan is very low, indicating a low affinity for protein binding

Description of key information

A toxicokinetics assessment provided by Charles River Laboratories sets several conclusions:

Absorption is estimated to be 10 % by oral and dermal route, and 100 % by inhalation.

Once absorbed, distribution of the substance throughout the body is expected to be limited based on its very low water solubility, relatively high log Pow and moderate molecular weight. Orally absorbed Tetradecafluorohexane may be metabolized in the gastrointestinal tract or the liver and excreted through bile and urine. As a very volatile substance, it may be excreted through exhaled air (1). Based on its relatively high partition coefficient (log Pow ≥ 4.5), Tetradecafluorohexane may accumulate in adipose tissue (intracellular concentration may be higher than the extracellular concentration). However, based on its very low water solubility and high molecular weight, the overall bioaccumulation potential of Tetradecafluorohexane is expected to be low.

(1) Parkinson A. In: Casarett and Doull’s Toxicology, The basic science ofpoisons. Sixth edition. Ed. C.D. Klaassen. Chapter 6: Biotransformation of xenobiotics. McGraw-Hill, New York, 2001.

In addition, toxicokinetics of tetradecafluorohexane (perflexane, PFH) is described in the new drug application dossier of AF0150, previously evaluated by US-FDA.

AF0150 is tetradecafluorohexane in lipid microspheres, designed for IV injection after suspention in water. According to AF0150 NDA dossier, lipid microsphere are destroyed rapidly, liberating PFH in blood.

Therefore, toxicological data on AF0150 appears to be relevant for tetradecafluorohexane registration under REACH.

IV injection and embedding in lipid microspheres dramatically increases tetradecafluorohexane bioavailability and half-life in blood.

PFH is rapidly eliminated in expired air after being liberated in blood.

Only one pharmacokinetic study was conducted in rats to determine the kinetic profiles of perflexane (PFH) in expired air and blood, and to estimate pharmacokinetic parameters of AF0150. The animais received a single bolus intravenous injection of AF0150 (PFH in lipid microspheres) at 20 mg/kg (26-fold PCD based on the body surface area) followed by 48-hour observation of PFH in expired air and blood (from femoral vein).

PFH elimination profiles in expired air revealed that about 90% of the administrated PFH was excreted from lungs within the first 3 hours post dosing and almost completely eliminated within 48 hours. PFH in blood had the same profile as in expired air, with a two-compartment model. PFH levels decreased by 78% within the first 2 minutes post dosing, and became non-detectable by 24 hours. The terminal elimination half-life of blood PFH was about 88 minutes based on the pooled data from individual animais.

The fate of the other AF0150 components was not addressed:

DMPC (1,2-dimyristoyl-sn¬glycero-3-phosphocholine), HES (m-hydroxyethyl starch) and Poloxamer-188 are other components in the AF0150 formulation, and their pharmacokinetics was not investigated. Some literature and a brief review regarding the pharmacokinetics of DMPC¬containing liposomes. In the clinical study cited by the sponsor, IV injection of 99mTc¬lyposome composed of DMPC and DMPG (dimyristoylphosphatidylglycerol) showed clearance of the liposome by macrophages of liver and spleen (2). Based on the literature report, due to nature of DMPC as a phospholipid and its minimal contribution into blood phospholipid pool (400-1000-fold less) after IV administration of 200 mg AF0150, the sponsor concluded that DMPC is safe.

Therefore, role of DMPC in the toxicokinetics of AF0150 is not assumed to change PFH.

No distribution and metabolism studies on AF0150 and/or PFH were submitted with the AF0150 US-FDA NDA dossier. The sponsor stated that there was no metabolites of PFH in urine and tissues in rat according to a literature report (1).

In the supporting literature article (1), PFH was administrated to rats by inhalation (2-hours exposure) instead of intravenous injection. Besides, there was no coadministration of other amphiphilic compounds formulated in AF0150 such as DMPC, HES and Poloxamer-188, confering to this study a particular relevance in the context of the registration of PFH (tetradecafluorohexane).

Polozamer-188 is a nonionic surfactant with a molecular weight of 8350. It is an approved drug and has been used orally for stool-wetting and stool-softening in the clinical setting. However, the pharmacokinetics and safety via intravenous administration are unknown.

Hydroxyethyl starch (HES) is commonly used for plasma volume expansion, and FDA-approved HES product includes Hetastarch and Pentastarch. Literature reported that HES was taken up by macrophages and parenchymal cells in organs, which frequently resulted in cell vacuolation (3-6). It was also found that species-dependent elimination of HES and clearance of HES from spleen and liver was slower in rats than in dogs. These may partially explain why vacuolated macrophages were observed in rats but not in dogs following AF0150 administration.

In conclusion, systemic exposure to tetradecafluorohexane by oral, dermal, or pulmonary route is expected to be negligible due to poor solubility in blood and rapid elimination by exhalation.

References

1.       Dodd DE et al: Metabolism and pharmacokinetics of selected halon replacement candidates. Toxicol Letter 68: 37-47, 1993.

2.       Lopez-Berestein G et al: Clinical Pharmacology of 99mTc-labeled liposomes in patients with cancer. Cancer Research 44: 375-378, 1984.

3.       Bogan RK et al: Fate of 14C-labeled hydroxyethyl starch in animais. Toxicol Appl Pharm 15: 206-211, 1969

4.       Hulse .IP et al: Elimination of High molecular weight hydroxyethyl starch in rats. Res Comm Chem Path Pharm 29: 149-158, 1980

5.       Lindbald G: The toxicity of hydroxyethyl starch: investigation in mice, rabbits and dogs. Proc Eur Soc Study Drug Tox 11:128-144, 1970.

6.       Thompson WL et al: Intravascular persistence, tissue storage, and excretion of hydroxyethyl starch. Surg Gynec Obstet 131: 965-972, 1970.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100