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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Limited details available on results
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
three-generation reproductive toxicity
Remarks:
based on test type
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
The primary report was not available for review but the data has been reviewed by the World Health Organisation (WHO) experts who have agreed that no effects or dominant lethality was found at either dose level tested.
Qualifier:
no guideline followed
Principles of method if other than guideline:
In a three-generation, oral gavage study in rats using CFC-12 (in corn oil) at average doses of 15 and 150 mg/kg per day. Limited details available but the data has been reviewed by the World Health Organisation (WHO) experts.
GLP compliance:
not specified
Remarks:
likely pre-dates the GLP standards
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Charles River CD
Sex:
male/female
Details on test animals or test system and environmental conditions:
Not specified
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
In a three-generation, oral gavage study in rats using CFC-12 (in corn oil) at average doses of 15 and 150 mg/kg per day
Details on mating procedure:
Not specified
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Not specified
Duration of treatment / exposure:
Not specified
Frequency of treatment:
Not specified
Details on study schedule:
Not specified
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
15 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
No. of animals per sex per dose:
50 /sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
Male and female rats were given Freon 12 in doses of 15 or 150 mg/kg by intubation. The rats were then bred and evaluated for fertility, corpora lutea, implantation sites, resorption sites, and number of live fetuses per litter.

Groups of 50 males and 50 females of the F1a generation remained in the test for 2 years, with an interim killing at 1 year.
Animals received CFC-12 in corn oil or corn oil alone daily by gavage for 6 weeks, and 5 times/week thereafter.

Dominant Lethal assay, part of a reproductive toxicity study:
The F0 animals of the reproduction study were mated to initiate an F1b litter. Animals were treated with the test substance gavage until pregnancies were terminated in mid-term to give a dominant lethal assay
Positive control:
Not specified (not required)
Parental animals: Observations and examinations:
Not specified
Oestrous cyclicity (parental animals):
Not specified
Sperm parameters (parental animals):
Not specified
Litter observations:
Not specified
Postmortem examinations (parental animals):
Not specified
Postmortem examinations (offspring):
Not specified
Statistics:
Not specified
Reproductive indices:
Fertility, corpora lutea, implantation sites, resorption sites, and number of live fetuses per litter.
Offspring viability indices:
Number of live fetuses per litter.
Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
No effects on fertility index (percentage of matings resulting in pregnancy), no effects on gestation index (% of pregnancies resulting in birth of liver litters).
No dominant lethality was found at either dose level.
Key result
Dose descriptor:
NOEL
Effect level:
> 150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
(limited details available)
Clinical signs:
no effects observed
Description (incidence and severity):
No overt signs of toxicity.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
no significant differences between treated and control groups in survival and post-natal survival (survival after 4 days or 21 days)
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
in F1a parental generation (treatment started at 6 weeks of age): Body weight gain was depressed in the high-dose groups, particularly among the females.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
Slight decline in food efficiency in high dose females, compared to controls
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
No effects reported on fertility index of the second parental generation
No details provided on the unpublished study report reviewed by WHO.
Key result
Dose descriptor:
NOAEL
Effect level:
> 150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
(limited details available)
Key result
Critical effects observed:
no
Clinical signs:
not specified
Description (incidence and severity):
No effects on viability index (percentage of rats born that survived four days)
No effects on lactation index (percentage of rats alive at 4 days that survived to be weaned at 21 days)
Body weight and weight changes:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
no effects observed
Description (incidence and severity):
No dominant lethality was found at either dose level, indicating no chromosomal damage to germ cells.
Behaviour (functional findings):
not specified
No dominant lethality was found at either dose level.
Key result
Dose descriptor:
NOEC
Generation:
F1
Effect level:
>= 150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
No effects reported on the reproductive parameters of the F1 generation and no effects on postnatal survival
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Conclusions:
No dominant lethality was found at either dose level.
The substance is not considered to be classified for fertility effects.
Executive summary:

In a 3-generation oral study using CFC12 (in corn oil) at average doses of 15 and 150 mg/kg per day, Sherman (1974) found no adverse effects in reproductive capability as measured by the fertility index, gestation index, viability index and lactation index. No classification is applicable.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1974
Reference Type:
review article or handbook
Title:
MISCELLANEOUS FOOD ADDITIVES - DICHLORODIFLUOROMETHANE
Author:
Joint FAO/WHO Expert Committee on Food Additives
Year:
1975
Bibliographic source:
JECFA Toxicological evaluation of some food colours, thickening agents, and certain other substances; WHO FOOD ADDITIVES SERIES NO. 8

Materials and methods

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Charles River CD
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 years
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
15 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
No. of animals per sex per dose:
50
Control animals:
yes

Results and discussion

Results of examinations

Body weight and weight changes:
no effects observed
Description (incidence and severity):
Slight body weight reduction

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
>= 150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Remarks on result:
not determinable due to absence of adverse toxic effects

Applicant's summary and conclusion

Conclusions:
No adverse effects were observed in a 2-year chronic study in rats administered 15 or 150 mg/kg/day by gavage.