Registration Dossier

Administrative data

Endpoint:
additional toxicological information
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted under GLP conditions using methodology that is well accepted by organization responsible for fluorochemicals

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report Date:
2011

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Cardiac sensitization is considered to have occurred if the response to epinephrine is enhanced following administration of the test substance.

GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
gas under pressure: liquefied gas

Results and discussion

Any other information on results incl. tables

CLINICAL OBSERVATIONS AND SURVIVAL

All animals survived to the end of the study. After exposure to 50,000 ppm, vocalization during exposure, injected sclera and excessive salivation were noted in animal nos. 4935 and 4936. Tremors and reddened gums were noted for animal no. 4935 after exposure to 50,000 ppm, and convulsions were noted for animal no. 4936. These were the only 2 animals exposed to 50,000 ppm. After exposure to 35,000 ppm, tremors, injected sclera, reddened ears, excessive salivation and salivation-related findings (wet clear material and white frothy material around the mouth) were observed. These findings were considered test article-related due to the number of incidences. There were no other test article-related clinical findings. All other observations were limited to single animals, were not noted in a dose-related manner and/or were common findings for laboratory dogs of this age and breed.

BODY WEIGHTS

Body weights were collected for determination of doses only and were not analyzed for test article effects. Body weights ranged from 7.4 to 10.1 kg on the days of dosing.

ELECTROCARDIOGRAPHIC EXAMINATIONS

After exposure to 25,000 and 35,000 ppm, there were no signs of cardiac sensitization. Animal nos. 4938 and 4935 were not challenged with epinephrine following exposure to 35,000 ppm; background noise on the ECG precluded complete characterization of the potential cardiac sensitization response following administration of 35,000 ppm. Following the initiation of exposure to 50,000 ppm, animal no. 4935 exhibited tremors and animal no. 4936 exhibited convulsions. Only animal no. 4935 received any challenge doses of epinephrine (2 and 4 μg/kg), but the ECG data could not be evaluated due to artifacts and noise from the tremors. Therefore, the potential cardiac sensitization response following administration of 50,000 ppm could not be evaluated.

Applicant's summary and conclusion

Conclusions:
There was no evidence of cardiac sensitization to epinephrine in beagle dogs following inhalation exposure to the test substance at a concentration of 25000 ppm (2.5% or 132750 mg/m3). The cardiac sensitization potential following exposure to 35000 ppm (3.5% or 185850 mg/m3) and 50000 ppm (5.0% or 265500 mg/m3) could not be definitively evaluated due to the presence of tremors during exposure. Clinical findings of tremors, injected sclera and excessive salivation were observed at exposure levels of 35000 and 50000 ppm. Vocalization during exposure, reddened gums and convulsions were also noted following exposure to 50000 ppm, and evidence of salivation and reddened ears were noted after exposure to 35000 ppm.
Executive summary:

Test substance was administered via muzzle-only inhalation exposure as acute exposures (gas) at concentrations of 2.5%, 3.5% and 5.0% (25000, 35000 and 50000 ppm, respectively). One group of 6 male dogs was used on this study with a minimum of 48 hours between exposure concentrations for each animal. Each dog served as its own control. Baseline response to the epinephrine challenge doses were collected 3 days prior to exposure to the test gas. For the 25000 and 35000 ppm groups, animals were administered predetermined increasing doses of epinephrine (2, 4, 6 and 8 µg/kg) as bolus injections (approximately 0.1 ml/sec) via an appropriate vein beginning approximately 5 minutes following exposure to the test article. Epinephrine challenge bolus injections were administered a minimum of 3 minutes apart or until the electrocardiogram (ECG) of the animal returned to its normal baseline rhythm. For the 50000 ppm group, 2 animals were exposed to the test article; however, due to behavioral responses displayed by the animals, exposure was terminated and no other animals were exposed at 50000 ppm. Only 1 of the animals exposed to 50000 ppm was administered epinephrine after exposure, and cardiac data following epinephrine challenge were not evaluated at this exposure level. Following the final exposure, all dogs were returned to the stock colony. The animals were observed twice daily for mortality and moribundity. Detailed physical examinations were performed and individual body weights were recorded approximately weekly during the pretest period, at randomization and on exposure days. Electrocardiographic data were recorded continuously throughout the pre-exposure period, exposure to the test gas and throughout administration of the challenge epinephrine dose (total of approximately 33 minutes).

There were no test substance-related deaths. After exposure to the test substance at a concentration of 50000 ppm, vocalization during exposure, injected sclera, excessive salivation, tremors, convulsions and/or reddened gums were noted. After exposure to 35000 ppm, tremors, injected sclera, reddened ears and excessive salivation and salivation-related findings were observed. There were no signs of cardiac sensitization in the animals challenged with epinephrine after exposure to 25000 and 35000 ppm of test substance. However, the presence of ECG noise in 2 animals following administration of 35000 ppm precluded complete characterization of the potential cardiac sensitization response at this exposure level. Following the initiation of exposure to 50000 ppm, two animals exhibited severe clinical findings (including tremors and/or convulsions), and only one of these animals was administered epinephrine after exposure; therefore, cardiac data following epinephrine challenge were not evaluated at 50000 ppm. In conclusion, in beagle dogs exposed to the test substance by inhalation, clinical findings of tremors, injected sclera and excessive salivation were observed at exposure levels of 35,000 and 50,000 ppm. Vocalization during exposure, reddened gums and convulsions were also noted following exposure to 50,000 ppm test substance, and evidence of salivation and reddened ears were noted after exposure to 35,000 ppm. There was no evidence of cardiac sensitization following exposure to 25,000 ppm (2.5%); the cardiac sensitization potential following exposure to 35,000 and 50,000 ppm (3.5% and 5.0%, respectively) could not be definitively evaluated due to the presence of tremors during exposure.