Tetradecafluorohexane

Endpoint summary

Description of key information

An Acute toxicity study in rat by oral route was performed for Reach registration purpose (OECD TG 423).

Two studies available in published scientific litterature were available reporting no adverse effect in rats and pigs after exposure to tetradecafluorohexane by inhalation.

An acute toxicity study in rat by intravenous route was available in the New Drug Application dossier of AF150 evaluated by US-FDA. As AF150 is tetradecafluorohexane encapsulated in lipid microspheres to allow intravenous administration and to enhance the biodisponibility of tetradecafluorohexane, this study was considered relevant to assess the systemic toxicity of tetradecafluorohexane.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

The study will be available 29/07/2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

yes

Remarks:

maximum level of daily mean target humidity on two days = 72%. Not affecting the results.

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

yes

Remarks:

maximum level of daily mean target humidity on two days = 72%. Not affecting the results.

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

maximum level of daily mean target humidity on two days = 72%. Not affecting the results.

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

Identification: Tétradécafluorohexane
Appearance: Clear colourless liquid
Stable under storage conditions until: 21 February 2020 (expiry date)

Species:

rat

Strain:

Wistar

Sex:

female

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

A single dose of test item was administered to the appropriate animals by oral gavage on Day
1, using a syringe with a plastic gavage cannula attached.
The dose volume for each animal was based on the body weight measurement prior to dosing.
Dose volume (mL/kg body weight) was calculated as follows:
Dose level (g/kg) / spec.gravity or density (g/mL).
For calculation of dose volume a specific gravity of 1.688 was used, this was later amended to
1.669. Actual given dose based on the amended specific gravity was calculated to be 1977
mg/kg. As the difference between intended dose and actual dose is minor and no differences
in outcome are expected, the dose is reported throughout the report as 2000 mg/kg.
The dosing formulations were stirred continuously during dose administration.
Animals were deprived of food overnight (for a maximum of 20 hours) prior to dosing and
until 3-4 hours after administration of the test item. Water was available.

Doses:

2000 mg/kg

No. of animals per sex per dose:

3

Control animals:

yes

Remarks:

3

Details on study design:

4.8. Experimental Design
The toxicity of the test item was assessed by stepwise treatment of groups of 3 females. The
absence or presence of mortality of animals dosed at one step determined the next step, based
on the test procedure defined in the guidelines. The onset, duration and severity of the signs
of toxicity were taken into account for determination of the time interval between the dose
groups. The first group was treated at a dose level of 2000 mg/kg. Based on the results, one
additional group was dosed at 2000 mg/kg.
4.8.1. Administration of Test item
A single dose of test item was administered to the appropriate animals by oral gavage on Day
1, using a syringe with a plastic gavage cannula attached.
The dose volume for each animal was based on the body weight measurement prior to dosing.
Dose volume (mL/kg body weight) was calculated as follows:
Dose level (g/kg) / spec.gravity or density (g/mL).
For calculation of dose volume a specific gravity of 1.688 was used, this was later amended to
1.669. Actual given dose based on the amended specific gravity was calculated to be 1977
mg/kg. As the difference between intended dose and actual dose is minor and no differences
in outcome are expected, the dose is reported throughout the report as 2000 mg/kg.
The dosing formulations were stirred continuously during dose administration.
Animals were deprived of food overnight (for a maximum of 20 hours) prior to dosing and
until 3-4 hours after administration of the test item. Water was available.
4.8.2. Justification of Route and Dose Levels
The oral route was selected as it is a possible route of human exposure during manufacture,
handling or use of the test item.
The dose levels were based on the OECD test guidelines and were selected from the series 5
(lowest dose level), 50, 300 and 2000 (highest dose level) mg/kg body weight. The starting
dose level should be the one that is likely to produce mortality in at least some of the animals
and was selected based on available toxicity data of the test item.
4.9. In-life Procedures, Observations, and Measurements
4.9.1. Mortality/Moribundity Checks
Throughout the study, animals were observed for general health/mortality and moribundity
twice daily, in the morning and at the end of the working day. Animals were not removed
from cage during observation, unless necessary for identification or confirmation of possible
findings.
4.9.2. Clinical Observations
4.9.2.1. Postdose Observations
Postdose observations were performed at periodic intervals on the day of dosing (at least three
times) and once daily thereafter. The observation period was 14 days.
All the animals were examined for reaction to dosing. The onset, intensity and duration of
these signs was recorded (if appropriate). Signs were graded for severity and the maximum
grade was predefined at 3 or 4. Grades were coded as slight (grade 1), moderate (grade 2),
severe (grade 3) and very severe (grade 4). For certain signs, only its presence (grade 1) or
absence (grade 0) was scored.
4.9.3. Body Weights
Animals were weighed individually on Day 1 (predose), 8 and 15. A fasted weight was
recorded on the day of dosing.
4.10. Terminal Procedures
All animals were sacrificed by oxygen/carbon dioxide procedure at the end of the observation
period. All animals assigned to the study were subjected to necropsy and descriptions of all
internal macroscopic abnormalities were recorded.
5. ANALYSIS
All results presented in the tables of the report are calculated using values as per the raw data
rounding procedure and may not be exactly reproduced from the individual data presented.
The oral LD50 value of the test item was ranked within the following ranges: 0-5, 5-50, 50-
300 or 300-2000 mg/kg b.w. or as exceeding 2000 mg/kg b.w. The LD50 cut-off value was
established based on OECD guideline 423. No statistical analysis was performed (The
method used is not intended to allow the calculation of a precise LD50 value).
The results were evaluated according to:
 Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the
United Nations (2017) (including all amendments).
 Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16
December 2008 on classification, labelling and packaging of items and mixtures
(including all amendments).
6. COMPUTERIZED SYSTEMS
Critical computerized systems used in the study are listed below. All computerized systems
used in the conduct of this study have been validated; when a particular system has not
satisfied all requirements, appropriate administrative and procedural controls were
implemented to assure the quality and integrity of data.

7. RETENTION OF RECORDS
All study-specific raw data, documentation, study plan and final report from this study were
archived at the Test Facility by no later than the date of final report issue. At least five years
after issue of the final report, the Sponsor will be contacted.
Electronic data generated by the Test Facility were archived as noted above.

Statistics:

No statistical analysis will be performed (The method used is not intended to allow the calculation of a precise LD50 value).

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

Hunched posture, piloerection and/or chromodacryorrhoea (snout) were noted for the animals on Day 1.

Body weight:

The mean body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.
The incidence of slight body weight loss on Day 15 in one animal was considered not indicative of toxicity, based on the absence of any corroborative findings in this animal.

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of the animals.

TABLE 1 MORTALITY DATA

 

 

TEST DAY	1	1	1	2	3	5	6	7	8	9	10	11	12	13	14	15
HOURS AFTER TREATMENT	0	2	4
FEMALES 2000 MG/KG	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
FEMALES 2000 MG/KG	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-

   

TABLE 2 CLINICAL SIGNS

TEST DAY		1	1	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15
HOURS AFTER TREATMENT		0	2	4
	MAX GRADE
FEMALES 2000 MG/KG
ANIMAL 1
Posture Hunchedposture	(1)	1	1	1	-	-	-	-	-	-	-	-	-	-	-	-	-	-
Skin / fur
Piloerection	(1)	-	1	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
Secretion / excretion
Chromodacryorrhoea(Snout)	(3)	-	-	1	-	-	-	-	-	-	-	-	-	-	-	-	-	-
ANIMAL 2
Posture
Hunchedposture	(1)	1	1	1	-	-	-	-	-	-	-	-	-	-	-	-	-	-
Skin / fur
Piloerection	(1)	-	1	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
Secretion / excretion
Chromodacryorrhoea(Snout)	(3)	-	-	1	-	-	-	-	-	-	-	-	-	-	-	-	-	-
ANIMAL 3
Posture
Hunchedposture	(1)	1	1	1	-	-	-	-	-	-	-	-	-	-	-	-	-	-
Skin / fur
Piloerection	(1)	-	1	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-
Secretion / excretion
Chromodacryorrhoea (Snout)	(3)	-	-	1	-	-	-	-	-	-	-	-	-	-	-	-	-	-
ANIMAL 4
Posture
Hunchedposture	(1)	1	1	1	-	-	-	-	-	-	-	-	-	-	-	-	-	-
ANIMAL 5
Posture
Hunchedposture	(1)	1	1	1	-	-	-	-	-	-	-	-	-	-	-	-	-	-
ANIMAL 6
Posture
Hunchedposture	(3)	1	1	1	-	-	-	-	-	-	-	-	-	-	-	-	-	-

- = Sign not observed

TABLE 3 Body Weights (Grams)                  

 

SEX/DOSE LEVEL	ANIMAL	DAY 1	DAY 8	DAY 15
FEMALES 2000 MG/KG	1	145	182	188
	2	156	194	199
	3	166	205	213
	MEAN	156	194	200
	ST.DEV.	11	12	13
	N	3	3	3
FEMALES 2000 MG/KG	4	193	216	211
	5	180	212	219
	6	159	189	200
	MEAN	177	206	210
	ST.DEV.	17	15	10
	N	3	3	3

TABLE 4 Macroscopic Findings

                                                      

ANIMAL  ORGAN	FINDING	DAY OFDEATH
FEMALES 2000 MG/KG
1	No findings noted	Scheduled necropsy Day 15 after treatment
2	No findings noted	Scheduled necropsy Day 15 after treatment
3	No findings noted	Scheduled necropsy Day 15 after treatment
FEMALES 2000 MG/KG
4	No findings noted	Scheduled necropsy Day 15 after treatment
5	No findings noted	Scheduled necropsy Day 15 after treatment
6	No findings noted	Scheduled necropsy Day 15 after treatment

Interpretation of results:

GHS criteria not met

Remarks:

The oral LD50 value of Tétradécafluorohexane in Wistar rats was established to exceed 2000 mg/kg body weight. According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight. Based on these results, Tétradécafluorohexane does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).

Conclusions:

The oral LD50 value of Tétradécafluorohexane in Wistar rats was established to exceed 2000 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.
Based on these results, Tétradécafluorohexane does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).

Executive summary:

The objective of this study was to determine the potential toxicity of Tétradécafluorohexane, when given by oral gavage at a single dose to rats of a single sex at one or more defined doses to evaluate the potential reversibility of any findings.

The study was carried out in compliance with the guidelines described in:

·       OECD No.423 (2001)"AcuteOral Toxicity, Acute Toxic ClassMethod"

·       EC No 440/2008, partB: "AcuteOral Toxicity, Acute Toxic ClassMethod"

·       EPA, OPPTS 870.1100 (2002),"AcuteOralToxicity"

·       JMAFF Guidelines (2000), including the most recentrevisions.

 

Tétradécafluorohexane was administered by oral gavage to two consecutive groups of three female Wistar rats at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15).

 

No mortality occurred.

Hunched posture, piloerection and/or chromodacryorrhoea (snout) were noted for the animals on Day 1.

The mean body weight gain shownbythe animals over the study period was considered tobesimilar to that expected for normal untreated animals of the same ageandstrain. The incidence of slight body weight loss on Day 15 inoneanimal was considerednotindicative of toxicity, basedontheabsence ofanycorroborative findings in thisanimal.

No abnormalities were found at macroscopic post mortem examination of the animals.

 

The oral LD50 value of Tétradécafluorohexane in Wistar rats was established to exceed 2000 mg/kg body weight.

According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.

Based on these results, Tétradécafluorohexane does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

One GLP guideline study.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2005-2006

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Principles of method if other than guideline:

Methods: Lung injury was induced in 30 anesthetized and
mechanically ventilated pigs by means of central venous infusion
of oleic acid. Animals were assigned to one of the following
groups: (1) control or gas ventilation (GV), (2) 2.5% perfluorohexane
vapor, (3) 5% perfluorohexane vapor, (4) 10% perfluorohexane
vapor, or (5) PLV with perfluorooctane (30 ml/kg).
Two hours after randomization, lungs were recruited and positive
end-expiratory pressure was adjusted to obtain minimal
elastance. Ventilation was continued during 4 additional hours,
when animals were killed for lung histologic examination

GLP compliance:

not specified

Test type:

other: Trial to assess benefits in using tetradecafluorohexane in injured lungs

Species:

pig

Strain:

not specified

Sex:

female

Details on test animals or test system and environmental conditions:

All animal procedures were approved by the Institutional
Animal Care Committee and the Government of
the State of Saxony, Germany, and conformed to the
Guide for the Care and Use of Laboratory Animals.
15
Anesthesia
Thirty female pigs weighing 31.1 3.5 kg (range,
25–37 kg) were premedicated with ketamine (2–3
mg/kg intramuscular) and brought to the experimental
operation room, where an ear vein was punctured. After
that, the trachea was intubated with a cuffed endotracheal
tube (7.5 ID), and an esophageal catheter (Erich
Jaeger GmbH, Ho¨chberg, Germany) was placed and advanced
into the mid chest until optimization of the
position was performed (see Instrumentation and Measurement
Devices section). Thereafter, anesthesia was
deepened and maintained with midazolam (0.5- to
1-mg/kg bolus plus 1–3 mg kg1 h1 intravenous) and
ketamine (3- to 4-mg/kg bolus plus 5–10 mg kg1 h1
intravenous). Paralysis was achieved with 2 mg pancuronium
bromide administered intravenously every hour.
Volume status was maintained by means of the administration
of a crystalloid solution (E153; Serumwerk Bernburg
AG, Bernburg, Germany) at a rate of 10–15 mg
kg1 h1
, with a colloid solution (10% hydroxyethyl
starch; Fresenius Kabi Deutschland GmbH, Bad Homburg,
Germany) being given as necessary to keep the
hemoglobin concentration in blood approximately constant
(normovolemia).

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

head only

Vehicle:

air

Details on inhalation exposure:

Volume-controlled ventilation was initiated using an
anesthesia machine with a semiclosed circle system
(Cato®; Dra¨gerwerk AG, Lu¨beck, Germany). Ventilator
settings were as follows: fraction of inspired oxygen
(FIO2) of 1.0 (fresh gas flow of 4 l/min), PEEP of 5 cm
H2O, and inspiratory:expiratory ratio of 1:1.7, which
corresponds approximately to the physiologic value. We
also used tidal volumes (VT) of 9 ml/kg, which corresponds to an intermediary value between protective (6
ml/kg) and conventional ventilation (12 ml/kg). The reason
for choosing this value was that in our experience,
carbon dioxide elimination is easier to achieve while
keeping inspiratory plateau pressures lower than 35 cm
H2O. Respiratory rates were adjusted to an arterial carbon
dioxide tension (PaCO2) of 35–45 mmHg. Except for
PEEP, which was readjusted later (see Protocol for Measurements
section), all settings of the mechanical ventilator
were kept constant throughout the experiments.

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

6 h

Concentrations:

2.5%
5%
10%

No. of animals per sex per dose:

6

Control animals:

yes

Remarks:

Vehicle

Details on study design:

Protocol for Measurements
Figure 1 shows the time course of events. After instrumentation,
a period of 30 min was allowed for animals to
stabilize. Baseline measurements were then obtained
and injury was performed in 30 animals, as previously
described. After injury (time 0), animals were assigned to
one of the five therapy groups after opening sealed
envelopes (n 6/group): (1) control—no therapy with
perfluorocarbon or gas ventilation (GV), (2) therapy
with 2.5% perfluorohexane, (3) therapy with 5% perfluorohexane,
(4) therapy with 10% perfluorohexane, and
(5) PLV with perfluorooctane (30 ml/kg) (see Partial
Liquid Ventilation section). Two hours thereafter, measurements were repeated (time 2), and the lungs were
recruited by means of a continuous pressure of 40 cm
H2O during 30 s. To avoid derecruitment and stabilize
the lungs thereafter, PEEP was set at 20 cm H2O while
other respiratory parameters remained unchanged. After
that, PEEP was reduced in steps of 5 cm H2O up to the
start value, with periods of 3 min being allowed at each
level (20, 15, 10, and 5 cm H2O). Measurements of total
respiratory elastance (ERS EL ECW) and PaO2 were
taken at each step. After this procedure, recruitment was
repeated in the same manner, and PEEP was set at the
level corresponding to the lowest ERS level. If ERS values
were comparable between two steps (difference 5 cm
H2O/l), the higher PaO2 level was used to set PEEP.
Measurements were repeated 4 and 6 h after injury
(times 4 and 6, respectively). Except for PEEP, mechanical
ventilator settings were the same as before lung
injury. Finally, animals were killed by means of the intravenous
injection of 2 g thiopental and 50 ml KCl, 1 M.
Administration of Vaporized Perfluorohexane
Perfluorohexane (C6F14; ABCR, Karlsruhe, Germany)
with a purity of 95% was used in this work. This compound
was chosen because of its relatively low molecular
weight (338 amu) and unique physicochemical properties
among the perfluorocarbons, particularly the
relatively high vapor pressure (273 mmHg at 30°C),
which permits its administration in vapor form.22 Accordingly,
administration of perfluorohexane vapor was
accomplished by means of two standard bypass vaporizers,
type 19 n (Dra¨gerwerk AG, Lu¨beck, Germany),
which were modified by a scaled opening of the dosage
control cone. Vaporizers were connected in series in the
inspiratory limb of the anesthesia machine and opened
to permit mixing of perfluorohexane with the fresh gas
flow. Inspiratory and expiratory concentrations of per-
fluorohexane were measured continuously by the mass
spectrometer, ensuring a controlled application

Statistics:

Statistical Analysis
Values are given as mean SD. Paired Student t tests
were used to assess the effects of lung injury. Comparability
among groups at baseline and time 0, total amounts
of OA per group, PEEP levels after lung recruitment, and
histologic findings were tested with one-way analysis of
variance. Repeated-measures two-way analysis of variance
was used to determine the effects of therapies on
time course of variables (time, group, and time * group
effects). When significance was achieved, it was followed
by post hoc analysis (Student-Newman-Keuls test).
Statistical analysis was performed using SPSS, version
11.5 (SPSS, Chicago, IL), and significance was accepted
at P 0.05.

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

>= 100 000 ppm

Based on:

test mat. (total fraction)

Exp. duration:

6 h

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

No lethal event occured

Clinical signs:

other: No alteration

Body weight:

Not adressed

Gross pathology:

No alteration

Other findings:

Improved function of previously injured lung.

Interpretation of results:

GHS criteria not met

Conclusions:

No toxicity reported after 6h exposure to tetradecafluorohexane by inhalation.

Executive summary:

This study aimed to assess wether administration of perfluorocarbons as liquid during acute lung injury is beneficial.

Although this study was not designed to assess toxicity, as no toxic effect was reported in any treatment group, whereas animals where closely monitored, the conclusion can reasonably be derived from this study that 6h acute exposure to 10% tetradecafluorohexane by inhalation has no toxic potential in pigs.

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1992-1993

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Principles of method if other than guideline:

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.

GLP compliance:

not specified

Test type:

other: Metabolism and toxicokintics experiment

Species:

rat

Strain:

Fischer 344

Remarks:

and Sprafgue-Dawley

Sex:

male

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

Route of administration:

inhalation: gas

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

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

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

ca. 2 h

Concentrations:

1% (10 000ppm)

No. of animals per sex per dose:

8

Control animals:

yes

Remarks:

two control animals exposed to air

Details on study design:

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.

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

>= 10 000 ppm

Based on:

test mat. (total fraction)

Exp. duration:

2 h

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

No mortality observed

Clinical signs:

other: No clinical sign reported

Body weight:

not adressed

Gross pathology:

no effect reported

Interpretation of results:

GHS criteria not met

Conclusions:

No toxicity reported after 2h exposure to tetradecafluorohexane by inhalation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The two studies are well documented, meet generally accepted scientific principles, and thus are acceptable for assessment.
Although none of these studies were designed specifically to assess toxicity, the endpoints usually examinated in acute toxicity studies are assessed in both cases.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

No toxicity was observed after administration of tetradecafluorohexane in pigs and rats after acute exposure by inhalation, oral gavage, or intravenous injection.

As tetradecafluorohexane is not dermal irritant nor has known systemic toxicity, no acute dermal toxicity is expected.