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Administrative data

Endpoint:
in vivo mammalian germ cell study: cytogenicity / chromosome aberration
Remarks:
Dominant Lethal Assay/chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
Toxic effect type:
concentration-driven

No adverse effects were reported regarding reproductive parameters and/or reproductive organs based on tests conducted by the oral (3-generation study) and/or inhalation routes (2-year repeated dose toxicity study). There was no dominant lethal effect indicating no specific concern for male reproduction.

Endpoint conclusion:
no adverse effect observed
Endpoint conclusion:
no study available
Endpoint conclusion:
no study available

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. 

This study has been reviewed by the World Health Organisation (WHO) and international experts have agreed that no effects or dominant lethality was found at either dose level tested. 

No effects were observed on fetal development in rats or rabbits exposed by the oral or inhalation routes.

Endpoint conclusion:
no adverse effect observed
Endpoint conclusion:
no adverse effect observed
Endpoint conclusion:
no study available

Several studies conducted in the past in rats and rabbits were available and assessed as a weight of evidence because they did not fulfill the current standards and available documentation was limited. However the studies reports cited here were reviewed by international experts as part of the International Program on Chemical Safety and summarised in the Environmental Health Criteria document No.113: Fully halogenated chlorofluorocarbons (WHO/IPCS, 1990).

http://www.inchem.org/documents/ehc/ehc/ehc113.htm#PartNumber:7

 

One of the most relevant studies was undertaken, as part of a comprehensive toxicological program, to evaluate the embryotoxic and teratogenic potential of CFC-12 when administered by intragastric intubation to pregnant rats during the period of fetal organogenesis. 

Gastric intubation of dichlorodifluoromethane (CFC-12) to pregnant rats from day six through day fifteen of their gestation period, at average dose levels of 16.6 and 170.9 mg/kg/day, had no effect on the food intake and the gain in body weight of the mothers.

No clinical signs of toxicity were observed in any of the treated animals. The outcome of pregnancy, measured by the number of implantation sites, resorptions and live foetuses per litter, was not adversely affected by the treatment. The treatment did not affect the embryonal development as measured by weight and crown-rump length of the foetuses. The absence of any major external, skeletal, and soft tissue abnormalities in live foetuses and a similar incidence of spontaneous minor anomalies in the control and treated groups indicate that oral administration for CFC-12 was not teratogenic.

 

CONCLUSIONS

The absence of any effect on the number of implantation sites, resorptions, live foetuses per litter and mean weight and crown-rump length of the foetuses indicate that maternal feeding of CFC-12 was not embryotoxic under the conditions of this experiment.

Likewise, the absence of any major abnormalities in live foetuses and a similar incidence of spontaneous minor anomalies in the control and treated groups indicate that CFC-12 was not teratogenic.

 

Other supporting studies:

In studies of inseminated Wistar albino rats and albino rabbits, Paulet et al. (1974) administered a mixture of 90% CFC-12 (dichlorodifluoromethane) and 10% Freon 11 by inhalation for 2hr/day. Rats were exposed on days 4 to 16 of gestation, and rabbits on days 5 to 20. The mixture was administered in a 20% concentration (200,000 ppm). No indications of any embryotoxic, fetotoxic, or teratogenic changes were found when dams were sacrificed and foetuses removed on day 20 of gestation (rats) or day 30 of gestation (rabbits). No classification is applicable.

 

In a study of a mixture (10% CFC-11 and 90% CFC-12), groups of rats and rabbits were exposed by inhalation on days 4-16 (rats) or days 5-20 (rabbits) of gestation for 2 h/day at a concentration of 989 g/m3(200 000 ppm). No evidence of embryotoxicity, fetotoxicity, or teratogenicity was seen when rats and rabbits were sacrificed at 20 days (rats) or 30 days (rabbits) of gestation. In addition, offspring of the dams that were allowed to deliver naturally showed no evidence of toxicity relative to survival or growth (US EPA, 1983). (possibly the same study by Paulet et al).

 

In a study, groups of 25 to 27 pregnant Charles River rats were given CFC-12 in corn oil by gavage at doses of 16.6 or 179 mg/kg per day on days 6-15 of gestation. Neither dose induced any evidence of embryotoxicity or teratogenicity (Sherman, 1974).

 

In conclusion, CFC-12 did not show any evidence of reproductive or developmental toxicity. No classification is applicable.

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 CLP Regulation (EC No 1272/2008). No classification for reproductive or developmental effects is therefore required.

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

Principles of method if other than guideline:
- Principle of test: Dominant Lethal assay, part of a reproductive toxicity study.
- Short description of test conditions: 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
- Parameters analysed / observed: fetal mortality
GLP compliance:
not specified
Remarks:
Not likely (prior to GLP standards)
Type of assay:
rodent dominant lethal assay

Test material

Constituent 1
Chemical structure
Reference substance name:
Dichlorodifluoromethane
EC Number:
200-893-9
EC Name:
Dichlorodifluoromethane
Cas Number:
75-71-8
Molecular formula:
CCl2F2
IUPAC Name:
dichlorodifluoromethane
Test material form:
not specified
Details on test material:
Not specified

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:
- Vehicle used: corn oil
Duration of treatment / exposure:
F0 animals were mater to initiate an F1b litter. Animals were treated by gavage until pregnancies were terminated in mid-term to give a dominant lethal assay.
Frequency of treatment:
Daily treatment for several weeks (no other details)
Doses / concentrationsopen allclose all
Dose / conc.:
15 mg/kg bw/day
Remarks:
(or 0.2%)
Dose / conc.:
150 mg/kg bw/day
Remarks:
(or 2%)
No. of animals per sex per dose:
no data
Control animals:
not specified

Examinations

Evaluation criteria:
fetal mortality

Results and discussion

Test results
Key result
Sex:
male
Genotoxicity:
negative
Toxicity:
no effects

Applicant's summary and conclusion

Conclusions:
There was no evidence of adverse effects in the Dominant lethal assay, indicating that the substance did not cause chromosome damage to germ cells of the treated male rats.