Chlorotrifluoroethylene

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Data source

Reference

Reference Type:

publication

Title:

Toxicology of chlorotrifluoroethylene

Author:

Walther, Heinz; Fischer, Hans Dieter; Jaeger, J.; Kemmer, Ch.; Kunze, D.

Year:

1970

Bibliographic source:

Fluoride (1970) Vol. 3, No. 4, pp. 181-7.

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Groups of mice were exposed to air containing CTFE in concentrations of 1000, 3000 and 8000 ppm for several exposure durations.

GLP compliance:

no

Test type:

concentration x time method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Chlorotrifluoroethylene

EC Number:

201-201-8

EC Name:

Chlorotrifluoroethylene

Cas Number:

79-38-9

Molecular formula:

C2ClF3

IUPAC Name:

1-chloro-1,2,2-trifluoroethene

Test material form:

other: gas

Details on test material:

name of the substance as cited in the paper: chlorotrifluoroethylene (CTFE)
Purity: 99.59%

Specific details on test material used for the study:

Purity = 99.59%
Gas chromatografic analysis showed six-unspecified contaminats.

Test animals

Species:

mouse

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

no data

Administration / exposure

Route of administration:

inhalation: gas

Type of inhalation exposure:

not specified

Vehicle:

air

Details on inhalation exposure:

Groups of mice were exposed to 60 liters of air.
99.59% pure CTFE in concentrations of 0.1%, 0.3% and 0.8% was added to the air immediately before the air entered the inhalation chamber.
Throughout the experiment the air-CTFE mixture was changed twice every hour in order to maintain a constant concentration.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

Gas-chromatographic analysis

Duration of exposure:

>= 1 - <= 36 h

Remarks on duration:

C = 0.1 %(v/v) (4 groups) --> exp duration: 12, 16, 24 or 36 hours. C = 0.3 %(v/v) (4 groups) --> exp duration: 2.5, 4, 7 or 16 hours. C = 0.8 %(v/v) (5 groups) --> exp duration:: 1, 1.5, 2, 3 or 4,25 hours.

Concentrations:

0.1%, 0.3%, 0.8% (v/v)

No. of animals per sex per dose:

Not more than 20 mice / group

Control animals:

not specified

Details on study design:

Gropus of mice (<= 20 mice/group) were exposed to a mixute of air-CTFE in concentrations of 0.1, 0.3 and 0.8%.(v/v) CTFE for several exposure durations:
C = 0.1 %(v/v) (4 groups) --> exp duration: 12, 16, 24 or 36 hours.
C = 0.3 %(v/v) (4 groups) --> exp duration: 2.5, 4, 7 or 16 hours.
C = 0.8 %(v/v) (5 groups) --> exp duration:: 1, 1.5, 2, 3 or 4,25 hours.

Biochemical, optical, electro-microscopic studies and enzyme-histochemical examinations, especially on the liver and kidneys were carried out in order to establish the different phases of the toxic sequence.

Statistics:

no data

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

> 1 000 - < 3 000 ppm

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other:

Remarks:

based on the complete set of lethality data

Effect levels 2

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

2 430 ppm

Based on:

test mat.

95% CL:

> 2 257 - < 2 576

Exp. duration:

4 h

Remarks on result:

other:

Remarks:

Calculated by LogProbit analysis based on the complete set of lethality data

Mortality:

At concentration of 0.1% (v/v): 40%, 60%, 100%, 100% lethality occurred at 12h, 16h, 24h and 36h exposure.
At concentration of 0.3% (v/v) : 30%, 85%, 100%, 100% lethality occurred at 2.5h, 4h, 7h and 16h exposure.
At concentration of 0.8%(v/v): 75%, 100%,100%, 100%, 100% occurred at 1h, 1.5h, 2h, 3h and 4.25h exposure.
Following exposure to CTFE at the concentration at or above 0.3% (v/v) and an exposure time of 2 hours, the animals die very promptly.
At the concentration of 0.8% which produces only 10% immediate lethality after 2 hours exposure, all animals succumbed immediately if the exposure time was 4 hours.
Further reduction of the exposure time not only decreased the death rate but also altered the interval between exposure and death. Animals exposed for brief periods likewise die days after exposure (“late lethality”), which according to the Authors pointed to secondary cause of death not attributable to the primary toxicity of CTFE.
This variation occurs with increasing concentrations of CTFE after even short exposure.
All three stages of lethality occurred in some animals under the same conditions of concentration and time.

The complete set of lethality data are reproted in Table 1.

Clinical signs:

other: no data

Body weight:

no data

Gross pathology:

no data

Other findings:

BIOCHEMICAL and MORPHOLOGICAL FINDINGS:
- Kidneys: After a brief exposure of only 1/2 hour to 0.3% concentration of CTFE the partes rectae of the main epithelium of the kidneys showed impaired histochemical ferment activity namely that of the glycerol-phosphate dehydrogenase according to Mellgren and Blackstadt method, fixation according to Conklin and of the succinate dehydrogenase according to Pearse method. The blood level of the isocitrate dehydrogenase activity rised early and rapidly. From these findings the authors concluded that CTFE damages primarily the mitochondria.
Subsequently a rapidly progressive necrotizing nephrosis ensued which leaded to uremia. The delayed lethality was concurrent with a sharp rise of the blood urea nitrogen, a fact which emphasizes the importance of damage to kidneys in CTFE poisoning. Animals which survived showed regeneration of the epitheliurn and scar formation in the kidneys. Simultaneously, the blood urea nitrogen, the ICDH content of the blood and the enzyme-histochemical findings becomed normal.
-Liver: Upon electronmicroscopic examination, the first visible changes in the liver are electron-dense deposits in the mitochondria which seemed to be calcium deposits. They disappeared during the recovery period. Additional damage to the liver was identical with that due to other hepatotoxic agents. They consisted of glycogen and RNA deterioration and fatty degeneration of parenchymal cell. Formation of large vacuoles in the parenchymal cells of the peripheral lobules was typical of CTFE. CTFE was not designated as a specific hepatotoxic agent because the relatively liver-specific sorbit-dehydrogenase was only slighyly elevated in serum.
- Heart: In the latter stages of poisoning, the myocardium exhibited necrosis
- Lungs : The lungs showed no damage except for capillary hypereznia and localized bleeding. More extensive pathology seemed to become manifest only with a high CTFE concentration (more than 0. 3%) or may be caused by agents accompanying CTFE.

Any other information on results incl. tables

TABLE 1.

Lethality data.

0.1% (v/v) CTFE				0.3% (v/v) CTFE				0.8% (v/v) CTFE
Exposure duration (hours)	Observation period (hours)	total lethality (%)	Type of lethality	Exposure duration (hours)	Observation period (hours)	total lethality (%)	Type of lethality	Exposure duration (hours)	Observation period (hours)	total lethality (%)	Type of lethality
36	36	100	Immediate	16	16	100	Immediate	4.25	4.25	100	Immediate
24	64	100	Immediate + Follow-up	7	16	100	Immediate + Follow-up	3	4.5	100	Immediate + Follow-up
16	144	60	Immediate + Follow-up + Delayed	4	144	85	Immediate + Follow-up + Delayed	2	6	100	Immediate + Follow-up
12	144	40	Follow-up + Delayed	2.5	144	30	Follow-up + Delayed	1.5	60	100	Follow-up + Delayed
								1	144	75	Follow-up + Delayed

Applicant's summary and conclusion

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

CTFE mainly impars kidney functionality. Damages on miocardium and liver were also observed.
Basing on the complete set of lethality, the LC50 (4h, mice) appears to be between 1000 ppmV and 3000 ppmV.

Executive summary:

In the Walther H.et al. (1970) study, mice were exposed to CTFE concentration in air of 0.1, 0.3 and 0.8 % v/v (1000, 3000, 8000 ppm v/v) for different exposure periods ranging in duration from 12 to 36 hours for the exposure level of 1000 ppm, from 2.5 to 16 hours for the exposure level of 3000 ppm, from 1 to 4.25 hours for the exposure level of 8000 ppm. Biochemical, optical, electron-microscopic and enzyme-histochemical examinations were made.

Basing on the results the authors distinguished three stages of lethality to CTFE: the immediate lethality (which was originally named by the authors “Acute lethality”) referred to lethality occurred during exposure, the “follow-up lethality”, referred to lethality which corresponded closely to the effects observed for acute lethality, “late lethality” indicating a marked interval between exposure to CTFE and death.

At the concentration of 1000 ppm, for an exposure period of 12 hours, the lethality (follow-up and delayed) of 40% was observed. Immediate lethality was observed when the exposure period was 16 hours, with a total lethality of 60% (immediate, follow-up and delayed)

At the concentration of 3000 ppm, for an exposure time of 4 hours, the lethality (immediate, follow-up and delayed lethality) of 85 % was observed.

At the concentration of 8000 ppm, for an exposure period of 2,5 hours the lethality of 100 % was observed (follow-up and delayed), when the exposure period was 4,25 hours 100 % of immediate lethality was reported.

Basing on the lethality results, the LC50 (mouse, 4h) appears to be between 1000 ppm and 3000 ppm.

 

At 3000 ppm, after 30 min of exposure, damage on kidney ephytelium was observed, attribyuted by the authors to damages on mitochondria (enzyme-histochemical findings + increasing of ICDH blood level). Then, a rapidly progressive necrotizing nephrosis was observed. Survival animals showed regeneration of ephythelium within 6 days, (scar formation in the kidney). Simultaneusly blood urea nitrogen, and enzyme-hystochemical findings become normal.

According to Walther Het al.,1970, the immediate and follow-up lethality of CTFE should be attributed to, generalized damage of mitochondria which affect kidneys, liver and myocardium. Necrosis of myocardium was observed in the latter stage of the poisoning. The "delayed" lethality was attributed to the prolonged and serious damage to kidneys.