Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
05/AUG/93 - 07/JAN/94
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report date:
1994

Materials and methods

Test guideline
Guideline:
other: Guideline established by ministry of health and welfare (No. 1 Notification No. 24, 1989)
Deviations:
not specified
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
1,1,2,2-tetrafluoroethyl-2,2,2-trifluoroethyl ether
EC Number:
609-858-6
Cas Number:
406-78-0
Molecular formula:
C4H3F7O
IUPAC Name:
1,1,2,2-tetrafluoroethyl-2,2,2-trifluoroethyl ether
Test material form:
liquid
Specific details on test material used for the study:
Name: 1,1,2,2-Tetrafluoroethyl 2,2,2-Trifluoroethyl Ether
Chemical formula: CHF2CF2OCH2CF3
Molecular weight: 200.06
Density: 1.4789g/cm3 (23°C)
Purity: 99.9%
Boiling point: 56.22°C
Storage conditions: In a refrigerator
Stability: The lot used in this study was confirmed to be stable in an analysis conducted by the sponsor

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
SD strain rats were obtained from Charles River, Japan, Inc. on August 25 1993 and were acclimated and quarantined for 7-8 days. Five male rats for each group were selected from the animals adjudged to be of good health. The rats were 5 weeks old and their body weight ranged from 146-173g (within ±20% of the average weight on day of exposure). The test animals were identified by a number on their tail using an oil based ink. The cages were also identified by using labels that listed study number, sex, dose, animal number and name of the test substance etc.

The animal room was maintained at a temperature between 20-25°C, with a relative humidity of between 40-70% and air ventilation of approximately 12x per hour (all fresh air supply), throughout the entire observation period (including acclimation and quarantine). The lighting period was provided 12h per day (07:00-19:00). The test animals were housed at one or two per autoclaved polycarbonate cage (265W x 426D x 220H mm), equipped with hardwood chips, throughout the entire observation period (including acclimation and quarantine). From the day of exposure, a filter cap with clear resin was mounted on the front and back sides of the cage. The filter caps were changed bi-weekly and other equipment was changed once per week. All accommodation used to house the rats during the study was autoclaved.

The rats were given a pellet diet ad libitum (except during exposure when it was stopped), using a stainless steel feeder. Contaminants, such as pesticide residues, within the diet used were analysed by a third party and confirmed to be under the permissible range in the standard operating procedure of the laboratory. Tap water was also provided ad libitum, filtered through a 5um filter and disinfected by UV radiation, via a polycarbonate resin watering bottle of 700mL. Again, water supply was stopped during exposure. The water supply was analysed periodically and the analytical value obtained was confirmed to be within the range of the ordinance No.56 of the Ministry of Health and Welfare.

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
clean air
Details on inhalation exposure:
Exposure concentration settings: A preliminary study was conducted using 3 males exposed to an average concentration of 71157.3 mg/m3 (8700 ppm) for 70 minutes, in which all animals died. Struggling, increased urine volume and soiled fur were all observed. An additional preliminary study was then conducted using 2 males that were exposure to 817.9 and 4089.5 mg/m3 (100 and 500ppm respectively) for one hour respectively. No dead animals or any clinical abnormalities were observed. From these results, exposure concentrations in the study were targeted to 8179 and 24537 mg/m3 (1000 and 3000ppm).

Exposure conditions: The study used a small stainless steel chamber for nose-only exposure that has a volume of approx. 2L with inner and outer cylinders. The animals were restrained and were set on the outer cylinder wall of the chamber. Exposure was conducted by blowing air containing a designated concentration of the test substance from the inner cylinder for inspiration and by exhausting expiration from the outer cylinder. The exposure was conducted once four 4 hours.

Gas generation and exposure method: The test substance vapour was generated by a bubbling method that directly blows air (1kg/cm2) at the test substance (in a cylinder maintained at 5.0°C using a constant temperature bath), at a rate of between 11.3 and 37.0mL/min (measured by a mass-flow controller). The generated vapour was mixed with pressurised air, measured at a volume of 105mL/min by a mass flow controller, in a primary mixing jar. Following this, the mixed vapour was supplied to the chamber and measured at a volume of 1.1L/min by a mass flow controller in a secondary mixing jar. The chamber was ventilated with exhaust volume of 1.2-1.35L/min by a full ventilation method. The pressure within the chamber after animal placement was set at +0 to +2.5mmAq, compared with that of outside. Exposure initiation occurred at the point of setting the animal to the chamber, after the vapour concentration inside the chamber had achieve equilibrium.

Exposure concentration measurement: The vapour inside the chamber was collected by an airtight glass syringe at approximately 0.5, 2.0 and 3.5h after commencement of exposure. The sampled vapour was then analysed by vapour chromatography and then the vapour concentration in the air was calculated. A hydrocarbon meter continuously measured the vapour concentration in the exhausted air in order to confirm temporal concentration variations.

Measurement of environmental conditions in the inhalation chamber: Temperature and relative humidity (Toyama type thermo-hygrometer) and oxygen concentration (oxygen meter, galvanic cell type) were measured at the commencement of exposure and then at one hour intervals.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Remarks on duration:
The animals were exposed to the substance once for four hours
Concentrations:
Group 1: 7933.63 mg/m3 (970ppm)
Group 2: 24618.79 (3010ppm)
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
Observation during exposure was conducted as much as possible. Post exposure, the animals were observed with respect to their mortality, appearance and behaviour in one hour intervals for two hours. Clinical observations were then conducted once per day until 14 days post exposure.

All surviving animals were weighed with a balance for their body weight immediately before exposure and then on days 3, 7 and 14 after exposure (the day of exposure was labelled day 0). The animals that died during exposure were not weighed.

After termination of observation on day 14, the surviving animals were subjected to necropsy after euthanasia under intraperitoneal thiopental sodium. The animals were exsanguinated by severing of the abdominal aorta and were subject to necropsy as soon as they were dead. The major organs (heart, lung, liver, kidney, spleen and nasal cavity) were fixed by a 10% phosphate buffered formalin and preserved. The lungs of two animals and the kidney of one were microscopically examined after preparation of histopathological specimens.

Results and discussion

Preliminary study:
A preliminary study was conducted using 3 males exposed to an average concentration of 8700ppm (66,886mg/m3) for 70 minutes, in which all animals died. Struggling, increased urine volume and soiled fur were all observed. An additional preliminary study was then conducted using 2 males that were exposure to 100 and 500ppm (768.8 and 3844mg/m3) for one hour respectively. No dead animals or any clinical abnormalities were observed. From these results, exposure concentrations in the study were targeted to 1000 and 3000ppm (7688 and 23,064mg/m3).
Effect levelsopen allclose all
Key result
Sex:
male
Dose descriptor:
LC50
Effect level:
> 3 010 ppm
Based on:
test mat.
Exp. duration:
4 h
Key result
Sex:
male
Dose descriptor:
LC50
Effect level:
> 24 618.79 mg/m³ air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
2/5 animals in the 24618.79 mg/m3 (3010ppm) died 1 hour post commencement of exposure
Clinical signs:
other:
Body weight:
The animals that survived exposure had normal body weight gain by termination of observation.
Gross pathology:
During necropsy, dead animals had reddish lungs, dilation of the atrium and congestion of cerebellum aperture. In the surviving animals, one animal in the 7933.63 mg/m3 (970ppm) group indicated a large number of greyish patches on the kidney. Other surviving animals did not reveal any abnormalities.
During histopathological examinations, one animal in the 7933.63 mg/m3 (970ppm) group revealed focal inflammatory change in the lung. In the 24618.79 mg/m3 (3010ppm) group, one animal revealed moderate congestion and oedema in the lung. For the animal that presented with greyish patches in the kidney at necropsy, there were no abnormalities seen at the histopathological level.

Any other information on results incl. tables

The average test substance concentrations in the air were 7933.63 ± 81.79 mg/m3 (970 ±10ppm) and 24618.79 ± 81.79 mg/m3 (3010± 10ppm). Concentration variability was within 5% for the average concentration. Consequently, it was confirmed that the concentration was well controlled. The relative concentration also revealed stable vapour generation.

The temperature was recorded at 24°C and the relative humidity ranged from 60 -64%. Oxygen concentrations ranged from 20.7 -21.0%.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Minimum and median lethal concentrations were estimated from the mortalities at the end of the observation period. Two animals died at exposure concentration of 24618.79 mg/m3 (3010ppm). However, there were no dead animals at exposure concentration of 7933.63 (970ppm). From the results described, classification of the test substance toxicity based on the LC50 value was not clear in detail however, the test substance was classified as a non-toxic substance.
Executive summary:

A simplified acute toxicity study of 1,1,2,2-Tetrafluoroethyl 2,2,2-Trifluoroethyl Ether was conducted using 5 male Sprague Dawley strain rats for each group. The animals were exposed to the test substance once for 4 hours, by nose-only inhalation exposure. The test substance vapour was generated by passing pressurised air into the test substance and was exposed to rats using a small nose-only inhalation chamber with approx. 2L of inner volume. Exposure concentrations were set at 8179 and 24537 mg/m3 (1000 and 3000ppm respectively). As a result of the exposure, actual exposure concentrations were recorded at 7933.63 ± 81.79 mg/m3 (970 ±10ppm) and 24618.79 ± 81.79 mg/m3 (3010 ± 10ppm). The achieved concentrations were almost comparable to the target concentrations and were temporally stable.

Two males died in the 24618.79 mg/m3 (3,010ppm) group due to the exposure. Struggling, increased urine volume and soiled fur were all observed. Body weight of the surviving animals increased normally. In the necropsy, the dead animals had reddish lungs and in the histopathological examination, the dead animals showed moderate congestion and oedema in the lungs. All of these findings were considered non-specific changes. Additionally, there was dilation of the atrium, congestion of the cerebellum aperture and a large number of greyish patches on the kidney at necropsy, as well as local inflammatory change in the lung at histopathological examination. These findings were also considered to be non-specific changes.

From the findings documented above, it was concluded that the minimum lethal concentration of 1,1,2,2-Tetrafluoroethyl 2,2,2-Trifluoroethyl Ether was over 7933.63 mg/m3 (970ppm) and the median lethal concentration was over 24618.79 mg/m3 (3010ppm). In regards to the acute toxicity by nose-only inhalation exposure, the test substance was classified as non-toxic.

Categories Display