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Effects on fertility

Description of key information
No internal peri- and postnatal reproduction toxicity studies of Flufenaminsäurebutylester are available. 
Results of a peri- and postnatal reproduction toxicity study are cited in RTECS database (May 2011):
Oral, gestation day 17 - lactation day 20 (rat): NOAEL = 45 mg/kg
(Kiso to Rinsho. Clinical report (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku; KS Bldg., Tokyo 101, Japan) V.1- 1960- v. 13, p. 3302, 1979 (KSRNAM))
Effect on fertility: via oral route
Dose descriptor:
NOAEL
60 mg/kg bw/day
Additional information

The oral administration of 15, 30 or 60 mg/kg HF-264 (equivalent to Flufenaminsäurebutylester) 60 days (males) or 14 days (females) before mating until gestation day 7 had no influence on body weight chances, food intakes, fertility, reproductive performance of pregnant rats (average no. of corpora lutea, implants, resorption sites, dead fetuses, viable fetuses, preimplantation loss and implantation rate), fetal development and skeletal development of rat fetuses. Toxicological non relevant findings were slightly increased average placental weight in the high dose group, reduced number of variations in lumbar ribs in the mid dose group and reduced number of hypoplasia of sternebrae in the high dose group.


Short description of key information:
No internal fertility studies of Flufenaminsäurebutylester are available.
Results of a fertility study are published in the literature (May 2011):

Oral, 60 days (males) or 14 days (females) before mating - gestation day 7 (rat): NOAEL = 60 mg/kg
(Kiso to Rinsho. Clinical report (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku; KS Bldg., Tokyo 101, Japan) V.1- 1960- v. 13, p. 3279, 1979 (KSRNAM))

Effects on developmental toxicity

Description of key information
No internal developmental toxicity / teratogenicity studies of Flufenaminsäurebutylester are available. 
Results of developmental toxicity / teratogenicity studies are cited in RTECS database (May 2011):
Oral, gestation day 7-17 (rat): NOAEL maternal and developmental toxicity = 90 mg/kg
(Kiso to Rinsho. Clinical report (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku; KS Bldg., Tokyo 101, Japan) V.1- 1960- v. 13, p. 3288, 1979 (KSRNAM))
Oral, gestation day 6-18 (rabbit): NOAEL maternal and developmental toxicity = 120 mg/kg
(Acta Medica et Biologica (Niigata Univ. School of Medicine, 1 Asahimachi-dori, Niigata 951, Japan) V.1- 1953- v. 27, p. 33, 1979 (AMBNAS))
Additional information

In a preliminary test the oral administration to pregnant rats with doses of 120 mg HF-264 (equivalent to Flufenaminsäurebutylester)/kg/day from gestation day 7 - 17 led to mortality in 5/7 animals from gestation day 10 -15. In the main test the oral administration of 30, 60 or 90 mg HF-264/kg/day from gestation day 7 - 17 had no influence on mortality, body weight increase, the average no. of implants, viable fetuses, dead fetuses, viable fetuses and resorption sites and on the fetal development and skeletal development of rat fetuses. Toxicological non relevant findings were increased number of variations in lumbar ribs in the mid dose group. Further investigations revealed no perinatal and postnatal effects on rat dams treated with HF-264 and no toxicological relevant effects of HF-264 on body weight changes, postnatal development, wet organ weights and relative organ weights, emotional behavior in open-field test, motor activity and reproductive performance of rat pups born to dams treated with HF-264.

In a preliminary test the oral administration to non-pregnant female rabbits with doses of 60, 120, 240 and 480 mg HF-264 (equivalent to Flufenaminsäurebutylester)/kg/day led to mortality in 1/6 animals in the 60, 120 and 240 mg/kg dose groups and 5/6 animals in the highest dose group. Body weight and food intake were reduced in the two highest dose groups. In the main test 30, 60, 120 and 240 mg HF-264/kg/day were orally administered to pregnant rabbits from gestation day 6 - 18. 4 rabbits of the 240 mg/kg (toxic dose) group died during the experiment owing to their inability to to feed. In the other dams HF-264 had no influence on successful pregnancy rates, body weight gain, organ weights and food and water intake.There was no toxicological relevant difference in number of implants, live fetuses, immature fetuses, dead fetuses and mean fetal body weight. No malformations were found in the skeletal systems or the visceral organs of rabbit fetuses. External malformations were found in the 30 mg/kg dose group (1/77) and in the 240 mg/kg dose group (2/65). This represented no significant difference between the incidences in the treatment groups and the spontaneous occurence rate of congenital malformations. Congenital anomalies observed in the two fetuses of the 240 mg/kg group were most likely due to the severe disturbance of maternal homeostasis caused by the maternal toxic dose of HF-264 and are therefore not relevant.

Toxicity to reproduction: other studies

Additional information

In a preliminary test the oral administration of HF-264 (equivalent to Flufenaminsäurebutylester) to pregnant rats at doses of 30, 45, 60 and 90 mg /kg/day from gestation day 17 onwards led to mortality in 1/10 animals of the 60 mg/kg group and 3/10 animals of the 90 mg/kg dose group. In the main test the oral administration of 15, 30 or 45 mg HF-264/kg/day from gestation day 17 - lactation day 20 had no toxicological relevant influence on mortality, body weight gain and maternal delivery (e.g. successfully delivered rats, duration of pregnancy, average no. of implantation sites, live and dead pubs and sex ratio). Moreover, treatment of the dams with HF-264 had no effect on the viability, the body weight gain, the postnatal development, the biochemistry, the organ weights, the motor action, the emotional or learning behaviour and the reproductive performance of the F1 rat pups. Additionally, after mating of F1 pups no changes on body weight development during pregnancy and reprodutive sequence of F1 pregnant rats and on development and skeletal development of F2 rat fetuses were observed.

Justification for classification or non-classification

Based on the study results a classification according to Directive 67/548/EEC and Regulation (EC) No. 1272/2008 (CLP) is not required.

Additional information

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