Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via inhalation route
Dose descriptor:
245 440 mg/m³
Additional information

No studies assessing the effects of HFC 125 on fertility were available. However, Article 13 of REACH legislation states that, in case no appropriate animal studies are available for assessment, information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across.

The use of analogue approach for hydrofluorocarbons is justified and documented in the position paper "Use of read across in the human hazard assessment of hydrofluorocarbons (HFCs)", attached in the endpoint summary in Section 7 of the Technical Dossier (Toxicological information).

A combined fertility and developmental effects study with rats was available on the structurally related substance, 1,1,1,3,3 -pentafluorobutane (HFC 365mfc; TNO, 2001). Groups of 28 male and female rats were exposed to 0, 5000, 15000 and 30000 ppm of the test substance. Males were exposed during a 10 weeks premating period, females were exposed 2 weeks prior to mating 5 days/week, 6 h/day. Afterwards animals were cohabited (one male and one female per cage) for maximum one week of mating, during which they were still exposed 6 h/day. Pregnant females were exposed until day 15 of gestation and sacrificed on day 21. Fetus, placentas and reproductive organs were weighed and fetuses were examined after Caesarian section. The viscera and the skeletons of all fetuses were examined. Males were sacrificed after the mating period and testes and epididymides, including sperm parameters, were examined.

No statistically significant differences between the control group and the exposed groups concerning the number of corpora lutea, implantation sites, live and dead fetuses, early and late resorptions and pre-and post-implantation losses were observed. The sex ratio of teh fetuses was comparable amongst all groups. No statistically significant differences in gravid and empty uterus weight, ovary weight, carcass weight and net weight change of females were observed. Also no remarkable findings of the placenta and the mean placenta weight, as well as statistically significant difference in mean anogenital distance were found between the control and exposed groups. Upon fetal examination there were no treatment-related changes in external observations or fetal soft tissues. No statistically significant differences were observed among the control, low-, mid- and high-concentration groups in skeletal malformations and anomalies. Statistically significant differences found in variations, retardation in skeletal ossification and cartilage were considered not to be related to treatment.

Based on the results of the study, NOAEL for reproductive and developmental effects was set at 30000 ppm, corresponding to the highest tested concentration.

In addition, a dominant lethal assay with mice, performed according to the protocol similar to OECD guideline 478 (ICI Central Toxicology Laboratory, 1979) and a reproductive toxicity study with rats (Alexander et al., 1996) on another structural analogue of HFC 125, 1,1,1,2 -tetrafluoroethane (HFC 134a), were available for assessment. No adverse effects on fertility were noted in the dominant lethal assay in mice exposed to the test substance at concentration levels of 0, 1000, 10000, 50000 ppm for 6 hr/days during 5 days. In the reproductive toxicity study, pregnant female rats (F0 generation) were exposed to the test substance at concentrations of 0, 2500, 10000 and 50000 ppm from day 17 to 20 of gestation. Exposure recommenced at the same concentrations on day 1 post partum and continued until day 21 post partum. The females were allowed to litter and rear their young (F1 generation). On day 21, 1 male and 1 female F1 pup was retained from each of the 20 litters/group and raised to maturity. The selected F1 rats were mated when they were approximately 84 days old and, on day 20 of pregnancy, the females were terminated to allow the examination of their uterine contents and ovaries. The F1 males were also terminated at this time. No treatment-related effects on reproductive performance, maturation or development of the offspring were reported, resulting in NOAEL of 50000 ppm for effects on fertility.

Finally, gross pathology and histopathology examinations performed in several reproductive organs of males (testes, epididymis and prostate) and females (uterus, ovaries and vagina) in a 28 -day and a 90 -day inhalation studies in rats exposed up to 245440 mg/m3 HFC 125 did not reveal any adverse effects (Jap. Bioassay Lab., 1992 and Jap. Bioassay Lab., 1993).

In summary, based on the evidence from the available studies on the structural analogues 1,1,1,2 -tetrafluoroethane and 1,1,1,3,3 -pentafluorobutane, HFC 125 is considered to be not toxic for reproduction. The absence of any signs of toxicity to reproductive organs following subacute and subchronic exposure to 254440 mg/m3 HFC 125 further supports the conclusion of no concern for possible effects to reproduction.

Short description of key information:
Justification based on the outcome of repeated inhalation studies and read-across with 1,1,1,3,3-pentafluorobutane (HFC 365mfc) and 1,1,1,2-tetrafluoroethane (HFC-134a)

Effects on developmental toxicity

Description of key information
Developmental toxicity studies in 2 species
Effect on developmental toxicity: via inhalation route
Dose descriptor:
245 440 mg/m³
Additional information

Groups of 40 pregnant female rats were exposed to levels of 0, 5000, 15000 or 50000 ppm (0, 24544, 73632 and 245440 mg/m3) for 6 hrs/day during the gestation days 6-15 and sacrificed on day 20 of gestation (Masters et al., 1992).  Adult female rats exhibited an unsteady gait during the exposure period, but no other treatment-related signs were observed. 

No treatment-related findings were observed in litter size, embryofetal loss and litter and fetal weight in the rat study.  No statistically-significant differences in the incidence of foetal malformations, anomalies and variants were observed during visceral and skeletal examination of fetuses among the control and the treated groups.  The fetal and maternal NOAECs are both considered to be 50000 ppm for this study.

Groups of 24 pregnant female rabbits were exposed to levels of 0, 5000, 15000 or 50000 ppm (0, 24544, 73632 and 245440 mg/m3) for 6 hrs/day during the gestation days 6-18 and sacrificed on day 29 of gestation (Brooker et al., 1992).  Two animals in the control group and one in the 5000 ppm group were sacrificed due to the poor condition.  Another animal treated at 5000 ppm showed weight loss during the early days of exposure and aborted on days 20/21.  There were no other instances of abortion during the study.   Adults treated at 50000 ppm, but not at 5000 and 15000 ppm, showed reduced food consumption in comparison with the control.  No significant differences were observed in body weight gain.  No treatment-related findings were apparent at terminal autopsy.

A slightly increased incidence of early and late in utero deaths was observed at 50000 ppm in comparison with the control.  However, statistical significance was not achieved.  The results were also within background incidence when compared with 9 studies carried out by the same laboratory in 1991, except for total embryonic deaths at 50000 ppm (in which results were slightly higher than historical controls (1.5 /litter versus 0.7-1.4/litter in historical control).  The incidence of foetal malformation was 2/165, 1/193, 7/215 and 2/169 for 0, 5000, 15000 and 50000 ppm, respectively.  There was no evidence of any treatment-related morphological change or of increased incidence of visceral and skeletal anomalies or variants.  The maternal and fetal developmental NOAECs for this study were 50000 ppm.

Justification for classification or non-classification

No developmental toxicity was observed in pregnant rats and rabbits exposed up to 50000 ppm HFC 125. Although no fertility study is available for HFC-125, the outcome of repeated inhalation studies and the read across with the structural analogues HFC-134a and HFC 365mfc do not indicate any concern. No classification is deemed necessary.

Additional information