Sulphur hexafluoride

Endpoint summary

Description of key information

The available 90-day study did not result in any treatment-related changes in the parameters tested. Therefore, the concentration level of 120870 mg/m3 was considered to be the No-Observed-Adverse-Effect-Concentration (NOAEC) for systemic and local toxicity.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: approximately 7 weeks
- Weight at study initiation: 241 g (males) and 161 g (females)
- Fasting period before study:
- Housing: in macrolon cages with a bedding of wood shavings (Lignocel, Rettenmaier & Söhne GmbH&Co) and strips of paper (Enviro-dri) as environmental enrichment. 5 aninmals of the same sex per cage
- Diet: cereal-based (closed formula) rodent diet (VrF1 (FG)) from a commercial supplier (SDS Special Diets Services, Witham, England), ad libitum, except during the exposure
- Water: domestic mains tap-water suitable for human consumption, ad libitum, except during the exposure
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 40-65; occasionally, the relative humidiy briefly exceeded 65% after wet cleaning activities.
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

inhalation: gas

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Battelle tubes
Each exposure unit (Institute’s design) consisted of a cylindrical PVC column with a volume of ca. 70 litres, surrounded by a transparent hood. The test atmosphere was introduced at the bottom of the central column, and was exhausted at the top. Each column included three rodent tube sections of 20 ports each. The animals were secured in plastic animal holders (Battelle), positioned radially through the outer hood around the central column (males and females alternated). The remaining ports were closed. Only the nose of the rats protruded into the interior of the column. Based on experience, the animal's body does not exactly fit in the animal holder which always results in some leakage from the high to the low pressure side. By securing a positive pressure in the central column and a slightly negative pressure in the outer hood, which encloses the entire animal holder, air leaks from nose to thorax rather than from thorax to nose and dilution of test atmosphere at the nose of the animals is prevented. Animals were rotated each week with respect to the position in the column, viz. they were moved 5 places each time, and also weekly alternated between the upper and the middle section.

The inhalation equipment was designed to expose rats to a continuous supply of fresh test atmosphere. The test atmosphere for group 2 was generated by mixing a mass flow controlled amount of gaseous test substance with a mass flow controlled stream of humidified compressed air. Because of the relatively high concentration of test substance, an additional mass flow controlled stream of oxygen was added to ensure a sufficiently high and, compared to the control group, equal oxygen concentration. The exposure unit for the control animals was supplied with a mass flow controlled stream of humidified compressed air only. The generated test atmospheres (overall mean daily flows were 27.2 and 23.9 L/min for the control and the exposure group, respectively) were directed to the bottom inlets of the exposure units. At the top of the units the test atmospheres were exhausted. The animals were placed in the exposure units after stabilization of the test atmosphere.
The flows of humidified compressed air and oxygen at the settings chosen for the high dose group were used to calculate the flow of test substance necessary to reach the target concentrations. All flows were measured using volumetric flow meters (DryCal, Bios International Corporation, Butler, NJ, USA). Because the target concentration was given in ppm, the flow of test substance necessary to reach the target concentration follow directly from:
Test substance flow = total flow × concentration in ppm/1,000,000
The total flow consists of the flows of humidified air, oxygen and test material. The mass flow control unit for the test material was adjusted to the level computed using again the volumetric flow meters. The settings (as initially chosen or computed) of the mass flow controllers (Bronkhorst, Hi Tec, Ruurlo, The Netherlands) were checked each morning at the start of generation, and subsequently at regular intervals during exposure (six times a day).

TEST ATMOSPHERE
- Brief description of analytical method used: photoacoustic infrared analysis (LumaSense Inc. USA) at a wavelength of 8.8 μm (filter UA0972).
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The actual concentrations of the test substance in the atmospheres were measured by photoacoustic infrared analysis (LumaSense Inc. USA) at a wavelength of 8.8 μm (filter UA0972). The responses of the analyzer (one response approximately every 40 seconds) were transmitted and recorded on a PC. The daily mean response for each exposure unit was calculated by averaging all values collected during exposure.

Duration of treatment / exposure:

90 days

Frequency of treatment:

6 hours/day, 5 days/week

Dose / conc.:

20 000 ppm (nominal)

Dose / conc.:

20 052 ppm (analytical)

No. of animals per sex per dose:

10/sex/concentration

Control animals:

yes

Details on study design:

- Dose selection rationale: The target concentration level for this sub-chronic study was selected on the basis of the results of a preceding combined repeated inhalatory exposure toxicity study with the reproduction/developmental toxicity screening test in rats (TNO Report V8551). In addition, in accordance with OECD guideline 413 in the absence of data-based limits for concentrations in subchronic inhalation toxicity studies, the acute limit of the Untied Nations Globally Harmonized System of Classification and Labelling of Chemicals are used (i.e., up to a maximum concentration of 5 mg/L for aerosols , 20 mg/L for vapors, and 20,000 ppm for gases).
- Rationale for animal assignment (if not random): computer randomization proportionately to body weight.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were observed daily in the morning hours by cage-side observations and, if necessary, handled to detect signs of toxicity. The animals were also observed about halfway through the 6-hour exposure period, in particular to monitor any breathing abnormalities and restlessness. All animals were thoroughly checked again in the afternoon. During weekends and on public holidays only one check per day was carried out. All abnormalities, signs of ill health, reactions to treatment and mortality were recorded.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Ophthalmoscopic observations were made prior to the start of exposure (on day -7), and towards the end of the exposure period (day 90) in all animals. Eye examination was carried out using an ophthalmoscope after induction of mydriasis by a solution of atropine sulphate.

BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of each animal was recorded five days before the start of exposure (these pre-test weights served as a basis for animal allocation, see paragraph 4.5), just before exposure on the first day (day 0), twice a week during the first 4 weeks (Mondays and Fridays) of the study and once a week (Fridays) thereafter during the remainder of the study. The animals were also weighed on the day before overnight fasting prior to necropsy, and on their scheduled sacrifice date in order to calculate the correct organ to body weight ratios.

FOOD CONSUMPTION:
- Food consumption of the animals was measured per cage by weighing the feeders. The results were expressed in g per animal per day. Food consumption was measured from day 0 over a 3-day period in the first week and subsequently over successive periods of 7 days, until the last week of exposure in which food consumption was measured over de 5-day period.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at necropsy from the abdominal aorta of overnight fasted rats.
- Anaesthetic used for blood collection: Yes (phenobarbital)
- Animals fasted: Yes, overnight (water was freely available)
- How many animals: all animals
- Parameters examined: haemoglobin, packed cell volume (PCV), red blood cell count (RBC), reticulocytes, total white blood cell count (WBC), differential white blood cell count (lymphocytes, neutrophils, eosinophils, basophils and monocytes), prothrombin time (PT), trombocyte count (platelet count), mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at necropsy from the abdominal aorta of overnight fasted rats.
- Anaesthetic used for blood collection: Yes (phenobarbital)
- Animals fasted: yes, overnight (water was freely available)
- How many animals: all animals
- Parameters examined: alkaline phosphatase activity (ALP), aspartate aminotransferase activity (ASAT), alanine aminotransferase activity (ALAT), gamma glutamyl transferase activity (GGT), total protein, albumin, ratio albumin to globulin, urea, creatinine, fasting glucose, bilirubin total, cholesterol, triglycerides, phospholipids, calcium (Ca), sodium (Na), potassium (K), chloride (Cl), inorganic phosphate.

Sacrifice and pathology:

GROSS PATHOLOGY:
Yes, the weights of the following organs were determined (paired organs together) as soon as possible after dissection to avoid drying. Relative organ weights (g/kg body weight) were calculated from the absolute organ weight and the terminal body weight.
- adrenals, brain, epididymides, heart, kidneys, liver, lungs with trachea and larynx, spleen, testes, thymus, thyroid, ovaries, uterus

HISTOPATHOLOGY:
For histopathological examination, samples of the following tissues and organs of all animals were preserved in a neutral aqueous phosphate-buffered 4% solution of formaldehyde (10% solution of Formalin). The lungs (after weighing) were infused with the fixative under ca. 15 cm water pressure to insure fixation. The carcass containing any remaining tissues was
retained in formalin until completion of the histopathological examination and then discarded.
- adrenals,
- aorta,
- axillary lymph nodes,
- brain (brain stem, cerebrum, cerebellum),
- caecum,
- colon,
- epididymides,
- eyes (with optic nerve),
- exorbital lachrymal glands,
- femur with joint,
- heart,
- kidneys,
- liver,
- lungs/trachea/larynx,
- mammary glands (females),
- cervical lymph nodes,
- nasopharyngeal tissue (with nasal associated lymphoid tissue and teeth),
- nerve peripheral,
- oesophagus,
- olfactory bulb,
- ovaries,
- pancreas,
- parathyroids,
- pharynx,
- parotid salivary glands,
- pituitary,
- prostate,
- rectum,
- seminal vesicles,
- skeletal muscle,
- skin (flank),
- small intestines,
- spinal cord (cervical, mid-thoracic, and lumbar),
- spleen,
- sternum with bone marrow,
- stomach,
- sublingual salivary glands and submaxillary salivary glands,
- testes,
- thymus,
- thyroid,
- tongue,
- tracheobroncial (mediastinal) lymph nodes,
- ureter,
- urethra,
- urinary bladder,
- uterus (with cervix).

Slide preparation
Tissues to be examined were embedded in paraffin wax, sectioned and stained with haematoxylin and eosin.
 
Histopathological examination
All preserved tissues of all animals of the control and test material treated group were examined histopathologically (by light microscopy). The nasopharyngeal tissues were examined at six levels with one level to include the nasopharyngeal duct and the Nasal Associated Lymphoid Tissue (NALT), the larynx at three levels (one level to include the base of the epiglottis), the trachea at three levels (including a longitudinal section through the carina of the bifurcation), and each lung lobe at one level.

Statistics:

Post-treatment body weight data: ‘Ancova & Dunnett’s Test’ with ‘Automatic’ as data transformation method.
Pretreatment body weight, organ weight, haematology and clinical chemistry data: ‘Generalised Anova/Ancova Test’ with ‘Automatic’ as data transformation method.
Food consumption data: Student’s t- test.
Incidences of histopathological changes: Fisher’s exact probability test.
Tests are performed as two-sided tests with results taken as significant where the probability of the results is <0.05 or <0.01.

Clinical signs:

no effects observed

Description (incidence and severity):

There were no treatment-related clinical signs.

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No adverse exposure-related changes in growth were found in male animals during the entire 92 days. A slight, but statistically significantly reduced body weight gain was observed in female animals on days 20, 52 and 92. These observations were considered not to represent an adverse effect, as the effect is not increasing during the course of the study, but remains fluctuating around the level of significance.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

There were no noticeable differences in food consumption between the test group and the control group. The overall food intake was comparable between both groups.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Description (incidence and severity):

Ophthalmoscopy did not reveal any treatment-related changes.

Haematological findings:

no effects observed

Description (incidence and severity):

Apart from a slightly lower hemoglobin (Hb) concentration in the males and a slightly lower percentage reticulocytes in the females, no statistically significant changes in red blood cell or clotting variables were observed. Apart from a slightly lower absolute and relative number of basophils in male rats, no statistically significant changes in total or differential white blood cell counts were observed.
These observations are normal variation and considered not to represent an adverse effect.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

Analysis of the clinical chemistry parameters revealed the following statistically significant differences between the exposed group and the control group:
- A slight decrease in ASAT level in males. As commonly an increase - rather than a decrease - is associated with liver toxicity and given the fact that the other parameters representing liver function remained unchanged, no toxicological relevance was attached to the decreased ASAT level. In addition, the value was within the historical range established at the test facility.
- A slight increase in ratio Albumin/Globulin in females. This ratio is calculated from the amounts of total protein and Albumin. As no effects were found on both the amount of total protein and the amount of Albumin, it was considered to be a chance finding.
- A slightly higher Chloride concentration was found in females. This value however, was still within the historical background data range established at the test facility. Hence, this observation was also considered not to be toxicologically relevant.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Absolute organ weights (see Table 1)
No statistically significant differences in absolute organ weights were observed between the males of the control and treated group. In the females, the absolute weights of the lungs, heart, adrenals and liver were slightly lower than those of the control group. This is in line with the slightly lower body weight of the females in this group when compared to control group. No effects on relative organ weights were observed (see below) and therefore these findings were not considered treatment-related.

Relative organ weights (see Table 2)
In the males a slight but statistically significantly higher relative liver weight was found. This increase was not considered to be adverse as it was not associated with histopathological findings and no effects were seen in females. In the females, the relative brain weight was statistically significantly higher when compared to the control group. The weight of the brains is less sensitive to changes in body weight in comparison to other organs and is thus less affected by the slightly lower body weight of the females in the exposed group. Consequently, the relative higher brain weight was not considered to be an adverse finding.

Gross pathological findings:

no effects observed

Description (incidence and severity):

Macroscopic observations at necropsy revealed no treatment-related abnormalities.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Microscopic examination revealed no treatment-related abnormalities.

Histopathological findings: neoplastic:

no effects observed

Details on results:

Analysis of exposure conditions

Actual concentration:
The average (± standard deviation) of the daily actual mean concentrations as measured by photo-acoustic infrared analysis was 20,052 (± 34) ppm. This concentration was close to the target concentration of 20,000 ppm.

Nominal concentration:
The daily nominal concentration was calculated using the amount of test material used during the study (measured daily), the flows of humidified air and oxygen (measured weekly) and the time the test atmosphere was generated. The average (± standard deviation) of the daily nominal concentrations was calculated to be 20,388 (± 436) ppm. Combined with the actual concentration of 20,052 ppm the generation efficiency was 98%, which is as expected for a test atmosphere generated with a gaseous compound.

Measurement of temperature, relative humidity carbon dioxide and oxygen content
Mean temperature (± standard deviation) during exposure was 22.6 (± 0.3) °C for both groups. The temperature was below 20.0°C in group 1 once (during 2 minutes with a minimum of 19.9°C). Transgressions of the lower (19°C) and upper limit (24°C) did not occur.

Mean relative humidity (± standard deviation) during exposure was 45.6% (±2.2) and 42.8% (±1.4) for the control and exposed groups, respectively. Relative humidity exceeded the upper limit of 70% in the control group 1 on 3 days for a total period of 75 minutes (maximum: 70.6%). Relative humidity did not decrease below 30%.

The carbon dioxide concentration during exposure in the control unit was 0.443% on 13 October 2015 and 0.550% on 11 January 2016. These values were 0.394% and 0.455% for the exposure unit. Likewise, and on these dates, oxygen concentrations were 20.2% and 19.8% in the control unit and 20.3% and 20.0% in the exposure unit.

Dose descriptor:

NOAEC

Effect level:

20 052 ppm (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed at the highest dose level tested.

Critical effects observed:

no

Table 1: Absolute organ weights (Day 93: Relative to Start Date)

Sex: Male		Terminal body weight (g)	Brain (g)	Lungs (g)	Heart (g)	Adrenals (g)	Kidneys (g)	Liver (g)	Spleen (g)	Thymus (g)	Testes (g)	Epididymides (g)
Control	Mean SD N	346.13 19.16 10	2.108 0.063 10	1.420 0.091 10	0.978 0.069 10	0.0495 0.0088 10	1.982 0.163 10	7.043 0.610 10	0.5697 0.0837 10	0.2393 0.0534 10	3.638 0.321 10	1.287 0.117 10
20,000 ppm	Mean SD N	333.74 27.44 10	2.065 0.067 10	1.366 0.103 10	0.961 0.069 10	0.0486 0.0055 10	1.937 0.145 10	7.161 0.640 10	0.5558 0.1195 10	0.2528 0.0552 10	3.601 0.434 10	1.254 0.165 10

 

 

Sex: Female		Terminal body weight (g)	Brain (g)	Lungs (g)	Heart (g)	Adrenals (g)	Kidneys (g)	Liver (g)	Spleen (g)	Thymus (g)	Ovaries (g)	Uterus (g)
Control	Mean SD N	194.87 10.58 10	1.883 0.074 10	1.034 0.052 10	0.673 0.031 10	0.0683 0.0088 10	1.266 0.103 10	4.787 0.361 10	0.3828 0.0490 10	0.1967 0.0249 10	0.0934 0.0161 10	0.8251 0.4878 10
20,000 ppm	Mean SD N	181.33^A 8.69 10	1.862 0.073 10	0.967^B 0.068 10	0.634^B 0.045 10	0.0601^B 0.0080 10	1.198 0.098 10	4.334^B 0.448 10	0.3342 0.0545 10	0.1823 0.0358 9	0.0889 0.0135 10	0.6329 0.3071 10

^A: Dunnet 2 sided p < 0.01

^B: Dunnet 2 sided p <0.05

 

 

Table 2: Relative organ weights (Day 93: Relative to Start Date)

Sex: Male		Terminal body weight (g)	Brain (g/kg)	Lungs (g/kg)	Heart (g/kg)	Adrenals (g/kg)	Kidneys (g/kg)	Liver (g/kg)	Spleen (g/kg)	Thymus (g/kg)	Testes (g/kg)	Epididymides (g/kg)
Control	Mean SD N	346.13 19.16 10	6.107 0.387 10	4.103 0.157 10	2.830 0.210 10	0.1429 0.0240 10	5.727 0.384 10	20.33 1.04 10	1.642 0.196 10	0.690 0.138 10	10.520 0.848 10	3.729 0.394 10
20,000 ppm	Mean SD N	333.74 27.44 10	6.223 0.516 10	4.098 0.174 10	2.888 0.203 10	0.1457 0.0131 10	5.819 0.400 10	21.47^B 1.01 10	1.655 0.245 10	0.756 0.143 10	10.841 1.418 10	3.769 0.515 10

 

 

Sex: Female		Terminal body weight (g)	Brain (g/kg)	Lungs (g/kg)	Heart (g/kg)	Adrenals (g/kg)	Kidneys (g/kg)	Liver (g/kg)	Spleen (g/kg)	Thymus (g/kg)	Ovaries (g/kg)	Uterus (g/kg)
Control	Mean SD N	194.87 10.58 10	9.682 0.519 10	5.312 0.244 10	3.463 0.257 10	0.3503 0.0402 10	6.502 0.483 10	24.55 0.85 10	1.964 0.228 10	1.011 0.123 10	0.4787 0.0733 10	4.270 2.575 10
20,000 ppm	Mean SD N	181.33^A 8.69 10	10.287^B 0.557 10	5.333 0.269 10	3.495 0.155 10	0.3323 0.0486 10	6.608 0.447 10	23.88 1.98 10	1.837 0.29 10	0.999 0.171 9	0.4916 0.0822 10	3.531 1.878 10

^A: Dunnet 2 sided p < 0.01

^B: Dunnet 2 sided p <0.05

 

Conclusions:

Under the conditions of the current study, inhalation exposure to 20,052 ppm SF6 induced no adverse effects. Thus, the No-Observed-Adverse-Effect-Concentration (NOAEC) for sub-chronic inhalation exposure to SF6 in rats was 20,052 ppm which corresponds to 120870 mg/m3.

Executive summary:

The sub-chronic toxicity of sulphur hexafluoride was studied in a 90-day inhalation toxicity study in Wistar rats. Two groups of 10 male and 10 female rats each were exposed by nose-only inhalation exposure to 0 (control) or 20,052 ( ± 34) ppm SF6 for 6 hours/day, 5 days/week over a 13-week period (65 exposure days). Animals were sacrificed on the day after the last exposure. The administration of the test material at a dose of 20,052 ppm was well tolerated and did not result in toxicologically relevant changes in the general condition, growth, food consumption, hematology, clinical chemistry, organ weights or macroscopy and microscopy of organs and tissues. Based on these observations, the No-Observed-Adverse-Effect-Concentration (NOAEC) was determined to be 20,052 ppm for sub-chronic inhalation exposure to SF6 in rats which corresponds to 120870 mg/m3.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

120 870 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

GLP Guideline study

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

As sulphur hexafluoride is a gas, oral and dermal routes of exposure are considered to be irrelevant.

In the available 28-day inhalation study with reproductive and developmental toxicity screening, performed under GLP and according to OECD guidelines (TNO, 2009), groups of 12 male and female Wistar rats were exposed to a limit (analytical) concentration of 302687 mg/m3 (target concentration of 50000 ppm) SF6 and air (control group) for 6 hours/day daily. Males were exposed for at least 2 weeks prior to mating, during mating and after the mating period at least until the minimum total exposure period of 28 days has been completed, while females were exposed for at least 2 weeks prior to mating, during mating and up to gestation day 19. Prior to the end of the premating period, 5 rats/sex/group were fasted overnight and blood was taken for haematology and clinical chemistry. In addition, Functional Observational Battery (FOB) tests, including assessment of grip strength and sensory reactivity to stimuli of different types, and spontaneous motor activity measurements were performed in 5 males/group prior to the end of dosing and 5 females/group prior to day 4 of lactation. Males were sacrificed after 29 days of exposure; females at day 4 of lactation or shortly after.

The amount SF6 detected in the blood samples of the SF6-exposed animals ranged from 1.3-3.6 µg/ml blood (mean 2.3+0.7). No mortalities or exposure-related clinical observations were observed. Weekly detailed clinical observation and neurobehavioural testing did not indicate an exposure-related effect. No exposure-related differences were observed on body weight and food consumption. No relevant differences were observed on haematology and clinical chemistry between the control and the SF6-exposed group. The organ weights of the control and SF6-exposed group recorded in 5 animals/sex/group: adrenals, brain, heart, kidneys, liver, lung, spleen, stomach and thymus were comparable. Microscopic examination of the testes, epidymides, seminal vesicle, prostate, uterus and ovaries of 12 animals/sex/group did not reveal any treatment-related effects. Microscopic examination of the adrenals, brain, caecum, colon, femur, heart, kidneys, larynx, liver, lung, nasal cavity, rectum, small intestines, spinal cord, spleen, stomach, thymus, thyroid, trachea/bronchi, and trachea/bronchial lymph nodes in 5 animals/sex/group did not reveal treatment-related histopathological changes in any of the sampled organs and tissues. Based on these results, the NOAEC was set at 302687 mg/m3.

 

The sub-chronic toxicity of sulphur hexafluoride was studied in a 90-day inhalation toxicity study in Wistar rats.Two groups of 10 male and 10 female rats each were exposed by nose-only inhalation exposure to 0 (control) or 20,052 (± 34) ppm SF6 for 6 hours/day, 5 days/week over a 13-week period (65 exposure days). Animals were sacrificed on the day after the last exposure. The administration of the test material at a dose of 20,052 ppm was well tolerated and did not result in toxicologically relevant changes in the general condition, growth, food consumption, hematology, clinical chemistry, organ weights or macroscopy and microscopy of organs and tissues. Based on these observations, the No-Observed-Adverse-Effect-Concentration (NOAEC) was determined to be 20,052 ppm for sub-chronic inhalation exposure to SF6 in rats which corresponds to 120870 mg/m3.

Justification for classification or non-classification

Based on the NOAEC of 120870 mg/m³ for rats obtained in the sub-chronic (90 -days) inhalation toxicity study, classification of sulphur hexafluoride is not warranted in accordance with EU classification, Labelling, and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.