Registration Dossier

Administrative data

Endpoint:
specific investigations: other studies
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)

Data source

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

Materials and methods

Principles of method if other than guideline:
Adrenaline was administered to dogs by intravenous injection before and during inhalation of the test substance. The effect of the adrenaline on the ECG pattern was examined. Positive evidence of cardiac sensitisation was observed as the presence of multiple multifocal ectopic beats or ventricular fibrillation following adrenaline administration during inhalation of the test substance. No such effect should be observed in the absence of the test substance.
GLP compliance:
yes
Type of method:
in vivo

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Purity: Not reported

Test animals

Species:
dog
Strain:
Beagle
Sex:
male

Administration / exposure

Route of administration:
inhalation: vapour
Vehicle:
other: diluent air
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Stage 1: intravenous injections of adrenaline at dose levels ranging from 1-12 µg/kg (challenge with adrenaline in the absence of any test gas)
Stage 2: inhalation of vapour at concentration levels 0, 0.1%, 0.5% and 1.0% of the test substance (with adrenaline); 17 minutes exposure.
Frequency of treatment:
Stage 1: individual response (up to approximately 10 unifocal ectopic beats) to adrenaline alone was targeted using a range of adrenaline doses.
Stage 2: 4 different exposure sessions with at least one calendar day between each exposure session.
Post exposure period:
None reported
Doses / concentrations
Remarks:
Doses / Concentrations:
0.1% (10309 mg/m3), 0.5% (51544 mg/m3), and 1.0% (103088 mg/m3)
Basis:
other: target level
No. of animals per sex per dose:
Stage 1: 9 male dogs (various concentrations of adrenaline)
Stage 2: 6 male dogs each at levels 0% (air only), 0.1% and 0.5% of the test substance, 1 male dog at 1.0% of the test substance
Control animals:
yes, concurrent vehicle

Results and discussion

Details on results:
At 0.1% of the test substance (all dogs tested), all dogs were negative and nothing abnormal was observed. At 0.5% of the test substance (all six dogs tested), all dogs showed some clinical signs during gas inhalation. The dogs showed various clinical signs of central nervous system toxicity, including shaking, rigidity, retching, vomiting, urinating, and defecating. At 1.0% of the test substance (one dog tested), the dog had severe convulsions which prevented the assessment of cardiac sensitisation potential.

Applicant's summary and conclusion

Conclusions:
The test substance was found not to have a cardiac sensitisation potential up to 0.5% v/v (51544 mg/m3) in air. At 1.0% v/v (103088 mg/m3) in air, the clinical response (severe convulsions) prevented the assessment of cardiac sensitisation potential.
Executive summary:

In the first stage of this study, dogs were given intravenous injections of adrenaline at dose levels ranging from 1 -12 µg/kg. The cardiac response of individual dogs to adrenaline injection was variable, ranging from several ectopic beats following administration of 1 µg/kg, to no ectopic beats following administration of 12 µg/kg. This observation confirms the importance of establishing an appropriate adrenaline dose for each dog before carrying out this type of study. In the second stage of the study, dogs were administered the test substance by inhalation of vapour through a face mask, in addition to adrenaline administration. The concentrations of the test substance in the air supply was 0, 0.1%, 0.5% and 1.0% v/v. Clear signs of test gas-related cardiac sensitisation in the dogs was looked at for all doses. The results of the second stage show that the test substance has no potential to cause cardiac sensitisation in dogs at concentrations up to 0.5% v/v. At a concentration of 0.5%, inhalation of the test substance causes marked clinical signs including shaking, muscular rigidity, retching, vomiting, urinary and faecal incontinence. At a concentration of 1.0%, exposure of one dog indicated that exposure at this level caused severe convulsions. The marked clinical response at this level prevented assessment of cardiac sensitisation.