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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

One study assessing toxicity to reproduction of AF150 (tetradecafluorohexane embeded in lipid microspheres) by iv route reports no effect relevant to toxicity for reproduction of tetradecafluorohexane administered by oral route.

One study reports no effect of administration of AF150 by iv route on implantation.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Study duration:

Justification for classification or non-classification

Summary of Reproductive Toxicity Study

No study was available assessing toxicity to reproduction of tetradecafluorohexane by oral route.

However, extensive data was available for the drug AF0150, which new drug application (NDA) was successfully assessed by US-FDA. AF0150 is tetadecafluorohexane in phospholipids, administered by intraveinous route. As discussed in toxicokinetics statement, formulation and route of administration of AF0150 is assumed to dramatically increase bioavalability of tetradecafluorohexane, without modifying further ADME since tetradecafluorohexane is not metabolized and rapidly eliminated in expired air.

IV AF0150 data was therefore considered relevant to assess t

oxicity to reproduction of tetradecafluorohexane by oral route.

Reproductive toxicity of AF0150 following intravenous injection was assessed in rats (fertility, teratology, pre-/post-natal toxicity) and in rabbits (teratology). Dose levels of 50-200 mg/kg/day were selected in both species.

Fertility and Early Embryonic Development (Segment I):The study was conducted in rats (25/sex) via IV injection of AF0150, from 2 weeks (females) and 4 weeks (males) pre-mating titi gestation day 7 (female). Animals were sacrificed on female gestation day 13. The dose levels of AF0150 were 50, 100 and 200 mg/kg/day. Slight decreases in male fertility (by 5%, without statistical significance) and mean epididymal sperm numbers (by 15%, p<0.05) were observed in the high dose groups (200 mg/kg/day), with the NOAEL of 100 mg/kg/day (HED: 16.2 mg/kg/day and HDM: 130-fold the PCD) for both findings. AF0150 had no significant effects on other reproductive performance (mating index, fertility index, pre-coital interval, and female estrous cycle) and male spermatogenesis (testicular sperm counts, sperm production rate, sperm motility and morphology) at any dose level as compared to saline. No remarkable findings were observed in females upon necropsy, on gestation day 13, including pre- and post-implantation fosses, numbers of viable embryos, implantation sites and corpora lutea. However, the high AF0150 dose, 200 mg/kg/day, did not result in maternal toxic signs, including changes on body weights, organ weights (brain, testis, ovary and pituitary) and food consumption. Minimal maternal toxicity should be generally expected in the high-dose group to confirm that appropriate doses were selected for the reproductive toxicity studies.

Teratology and Embryo/Fetal Development (Segment II):Two studies were conducted in rats (25 females) and rabbits (25 females) following IV injection of AF0150 at 50, 100, 200 mg/kg/day. The animals were dosed daily during the organogenesis period, from gestation day 6 through 17 (sacrificed on gestation day 20) for rats, and gestation day 7 through 20 (sacrificed on gestation day 29) for rabbits. There were no significant differences in fetal development, viability, body weights, sex ratio, corpora lutea number, implantation sites and post-implantation loss between AF0150-treated and control groups in either species. However, the fetal malformation incidence slightly increased in the 100 and 200 mg/kg/day groups in rabbits but not in rats as compared to the control group. These malformations included external, visceral (soft tissue) and skeletal anomalies. Percentage of fetuses with malformations was 1.9% in control rabbits, 3.7% and 5.9% in rabbits treated with 100 and 200 mg/kg/day AF0150, respectively. The NOAEL was therefore determined at 50 mg/kg/day. No maternal toxicity (clinical signs, body weight and food consumption changes, and macroscopic examination) was observed in either species at any AF0150 dose level, suggesting that a higher dose should have been used to produce minimal maternal toxicity. The NOAEL for maternal toxicity was 200 mg/kg/day (HDM: 259-fold in rats and 518-fold in rabbits).

Prenatal and Postnatal Development (Segment III):This study was conducted in rats (25 females) following daily IV injection of AF0150 at 50, 100 and 200 mg/kg/day from gestation day 6 through lactation day 20. AF0150, at all dose levels, had no significant maternal toxicity (clinical signs, body weight, food consumption and necropsy), pregnancy rate, gestation duration and parturition process. However, at the dose of 200 mg/kg/day, AF0150 decreased the live birth index (by 7% with p<0.05), and tended to decrease (no statistical significance but p values were not provided) postimplantation survival index (by 6.8%), mean live litter size (by 8%), live pup numbers (by 8.8%) and gestation survival index (by 5%). Stillbirths were increased from 0.3% (in the control group) to 7.7% (in the 200 mg/kg/day group) per litter (about 25-fold higher). There was also approximately 2-fold increase in total postnatal death and postnatal missing/cannibalized during the postnatal days 0-21 in the 200 mg/kg/day group. The NOAEL for neonate toxicity was 100 mg/kg/day. The offspring from AF0150-treated animals had no differences in physical and functional development as well as in behavior, from those from the control group. A fertility study on the offspring from the AF0150-treated groups showed no significant effects on fertility and mating indices in either sexes, nor on fetal development and morphology, as compared to the offspring from the control group.

Conclusion and Recommendation: Intravenous injection of AF0150 at the dose of 50 -200 mg/kg/d in rat had no significant adverse effects on fertility, teratology, embryonic (early and later) and fetal development. At the dose of 200 mg/kg/day in rabbits, AF0150 slightly increased incidence of external, visceral and skeletal malformations. Also at this dose in rats, lower neonate live birth and higher stillbirths were noted than in control group. In all 4 reproductive toxicity studies, the highest dose, 200 mg/kg/day, did not result in minimal maternal toxicity, suggesting that dose selection was not optimized.

Due to discrepencies in results across species, the low incidence of the events observed, the fact that effects were observed at high dose, and the maximization of bioavailibility of tetradecafluorohexane due to galenic and route of administration of AF0150, the relevance for human health of the toxicity to reproduction observed experimentally is considered very low.

In conclusion, tetradecafluorohexane should not be classified as toxic for reproduction.

Additional information