Registration Dossier

Administrative data

Description of key information

Sub-chronic and chronic inhalation toxicity and carcinogenicity is discussed.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: oral
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Taken from publically available data, and is considered accurate based on the registrants experience of the substance, and relates to chronic results. Conducted on a mixture containing the substance. Please note that a carcinogenicity study on the substance also exists; this is detailed below under Section 7.7.
Qualifier:
no guideline followed
Principles of method if other than guideline:
See "details on study design" listed below.
GLP compliance:
not specified
Limit test:
no
Species:
other: mice & dogs
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
Not specified
Route of administration:
inhalation
Type of inhalation exposure:
not specified
Vehicle:
not specified
Remarks on MMAD:
MMAD / GSD: Not specified
Details on inhalation exposure:
Not specified
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Dose concentrations are provided on the basis of calculated values.
Duration of treatment / exposure:
30 female mice were exposed for 23 months.
Adult dogs were exposed for 1 year.
Frequency of treatment:
30 female mice were exposed by inhalation 5 days/week.
Adult dogs were exposed 7 days/week.
Remarks:
Doses / Concentrations:
0 or 970 mg/kg-Mice.
Basis:
other: calculated value
Remarks:
Doses / Concentrations:
2240 mg/kg-Dogs
Basis:
other: calculated value
No. of animals per sex per dose:
30 female mice used in one experiment.
6 dogs in total, 3 of each sex used in the second experiment.
Control animals:
not specified
Details on study design:
In long term inhalation toxicity studies by Smith & Case (1973) mice and dogs were exposed regularly for brief periods to high levels of mixtures of CFC-11, CFC-12, CFC-114 and CFC-113 (ration of 24:49:25:1.1) and CFC-11, CFC-12, CFC-114 and Span 85, an emulsifier (24.5:50:25:0.5) respectively. In this study, 30 female mice were exposed by inhalation 5 days/week at levels of 0 or 970 mg/kg (calculated value) per day for 23 months. Dogs (3 of each sex) were likewise exposed 7 days/week at levels of 0 or 2240 mg/kg (calculated value) per day for 1 year.
Positive control:
Not specified
Observations and examinations performed and frequency:
Haematology, blood chemistry, and urinalysis - frequency not specified.
Sacrifice and pathology:
Performed but further information not specified.
Other examinations:
Not specified
Statistics:
Not specified
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
In this study 30 female mice were exposed by inhalation. No signs of toxicity were observed during the study and there was no evidence of lung tumours after the 23 months of exposure. When adult dogs (three of each sex) were exposed, some signs of toxicity, such as slight depression or drowsiness, were observed in dogs immediately after dosing but lasted only a few minutes. Tissue sections of the lungs did not show signs of toxicity or irritation from inhalation. Also, no changes were observed in haematology, blood chemistry, or urinalysis.
Dose descriptor:
NOEC
Effect level:
> 970 other: mg/kg per day
Based on:
other: calculated value
Sex:
not specified
Basis for effect level:
other: Mouse data
Dose descriptor:
NOEC
Effect level:
> 2 240 other: mg/kg per day
Based on:
other: calculated value
Sex:
male/female
Basis for effect level:
other: Dog data
Critical effects observed:
not specified
Conclusions:
Mice-No signs of toxicity were observed during the study and there was no evidence of lung tumours after the 23 months of exposure.
Dogs-Tissue sections of the lungs did not show signs of toxicity or irritation from inhalation. Also, no changes were observed in haematology, blood chemistry, or urinalysis.
Executive summary:

The toxicity of CFC-12 following repeated exposure by inhalation has been studied in the mouse and dog. In long-term inhalation toxicity studies by Smith & Case (1973), mice and dogs were exposed regularly for brief periods to high levels of mixtures containing CFC-12, at 49% and 50%, respectively. In this study 30 female mice were exposed by inhalation 5 days/week at levels of 0 or 970 mg/kg (calculated value) per day for 23 months. No signs of toxicity were observed during the study and there was no evidence of lung tumours after the 23 months of exposure. When adult dogs (three of each sex) were exposed 7 days/week at levels of 0 or 2240 mg/kg (calculated value) per day for 1 year, some signs of toxicity, such as slight depression or drowsiness, were observed in dogs immediately after dosing but lasted only a few minutes. Tissue sections of the lungs did not show signs of toxicity or irritation from inhalation. Also, no changes were observed in haematology, blood chemistry, or urinalysis.

On the basis of the dose levels noted in approximately 50% CFC-12 dose levels, no classification is required

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
970
Study duration:
chronic
Species:
mouse
Quality of whole database:
Values given above relate to mg/kg (calculated). Note that the carcinogenicity study detailed in section 7.7 is used for definitive CSA usage.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

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

In accordance with section 2 REACH Annex XI, studies via the oral and dermal route do not need to be conducted as the substance is a gas.

The toxicity of CFC-12 following repeated exposure by inhalation has been studied in the mouse and dog. In long-term inhalation toxicity studies by Smith & Case (1973), mice and dogs were exposed regularly for brief periods to high levels of mixtures containing CFC-12, at 49% and 50%, respectively. In this study 30 female mice were exposed by inhalation 5 days/week at levels of 0 or 970 mg/kg (calculated value) per day for 23 months. No signs of toxicity were observed during the study and there was no evidence of lung tumours after the 23 months of exposure. When adult dogs (three of each sex) were exposed 7 days/week at levels of 0 or 2240 mg/kg (calculated value) per day for 1 year, some signs of toxicity, such as slight depression or drowsiness, were observed in dogs immediately after dosing but lasted only a few minutes. Tissue sections of the lungs did not show signs of toxicity or irritation from inhalation. Also, no changes were observed in haematology, blood chemistry, or urinalysis.

On the basis of the dose levels noted in approximately 50% CFC-12 dose levels, no classification is required.

In addition, dogs, monkeys and guinea pigs were exposed to air containing 20 per cent by volume of dichlorodifluoromethane vapour for 7 to 8 hours daily on five days, and for four hours on the sixth day of each week during a 12-week period. During the exposure they were observed for unnatural signs or symptoms; change in weight; changes in red blood cells, hemoglobin, and white blood cells and their types; fatality and pathology indicative of deleterious action of the gas.

1. Exposure for 7 to 8 hours daily to 20 per cent dichlorodifluoro methane produces mild to moderate to marked generalised tremor in dogs and mild to moderate generalised tremor in monkeys. When they attempt to walk, they act very much like persons suffering from alcoholic ataxia. They react to light and stimuli and do not become unconscious. The maximum severity of symptoms is reached in the first 10 to 20 minutes of an exposure. A tolerance is developed with successive exposures as manifested by decrease in severity of the symptoms. Guinea pigs exhibit no significant symptoms.      

2. During the first two or three weeks of the test the weight and growth of some of the animals were slightly to moderately inhibited, but during the succeeding two to three weeks they regained and loss and thereafter maintained weight and growth similar to unexposed control animals.      

3. The number of red blood cells and hemoglobin tended toward a slight increase during the first two to three weeks of the test but thereafter was normal and similar to control animals; also, the number of white cells was the same as the controls. Differential white cell examinations showed a slight increase in the polymorphonuclear neutrophils and a slight decrease in lymphocytes in the blood of animals exposed to dichlorodifluoro methane. The number of eosinophils, basophils, lymphoblasts, endothelial cells, normoblasts, and Kurloff bodies was practically the same for both the animals exposed to dichloro-difluoro methane and the controls.      

4. No fatalities occurred among the dogs and monkeys. The fatality among the guinea pigs used for symptoms, weight, and fatality observations was two out of a group of 16 exposed to gas and one out of a group of 16 controls during the 12 -week test period, thus indicating no effects of exposure on fatality.      

5. Autopsies performed on all animals revealed no gross pathology attributable to the exposure to dichloro-difluoro methane.      

6. Pregnancy and bearing normal young were frequent among the guinea pigs exposed to dichloro-difluoro methane as among the controls. No abortions or abnormal foeti were observed.      

7. In so far as the results of animal experimentation serve as a measure of hazards to persons, the investigations described in this report has shown that the possibility of public health and accident hazards resulting from exposure to dichloro-difluoro methane when used as a refrigerant are remote.      

 

In addition, a carcinogenicity study on the substance was conducted. Three propellant chlorofluorocarbons, namely trichlorofluoromethane (FC11), dichlorodifluoromethane (FC 12), and chlorodifluoromethane (FC22) were administered by inhalation at a concentration of 5000, 1000 and 0 ppm, 4 hours daily, 5days weekly, for 104 and 78 weeks, to rats and mice, respectively.

As a result of this study, no unexpected treatment-related tumors were observed in rats exposed to FC11, FC12, and FC22. No important differences in the incidence of total benign and malignant tumors and of frequently occurring spontaneous tumors were observed in the rats exposed to the tested propellants. The incidence of all tumors and of some particular frequently occurring spontaneous tumors in mice showed a tendency to increase in animals exposed to FC11 and FC12.The increased incidence was usually observed in one sex and was not always dose-related, possibly due toalonger survival of the treated mice compared with controls.

 

Under the experimental conditions, and on the basis of statistical analysis and of the oncological evaluation of the results, FC11, FC12 and FC22 failed to show carcinogenic effects.

 

Value used for CSA (route: inhalation):

NOEC 24725 mg/m3 air (5000 ppm from the 2 -year carcinogenicity study in the rat)


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
This route of exposure is not applicable to the substance as a gas.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Not assessed. Local effects were not documented in the repeated dose study data available, and no further studies are deemed appropriate.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
This route of exposure is not applicable to the substance as a gas.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
This route of exposure is not applicable to the substance as a gas.

Justification for classification or non-classification

The above studies have all been ranked reliability 2 according to the Klimish et al system. This ranking was deemed appropriate because the studies were not conducted to GLP and are not in compliance with agreed protocols. However these are considered appropriate for use in assessment purposes in accordance with the criteria listed in Annex XI. As such, it is deemed appropriate to apply a weight of evidence approach based on similarity and animal welfare grounds.

The above results triggered no classification under the Dangerous Substance Directive (67/548/EEC) and the CLP Regulation (EC No 1272/2008). No classification for repeat exposure effects is therefore required.