Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via inhalation route
Dose descriptor:
NOAEC
417 mg/m³
Additional information

No animal studies were conducted with 2,4-pentanedione to investigate possible substance-related effects on the reproductive performance. In a subchronic inhalation study conducted in male and female F344 rats after exposure towards 0, 100, 300 and 650 ppm (nominal concentrations, corresponding to 0; 417; 1217 and 2711 mg/m3) no findings of pathological significance were noted in testes and epididymis of males as well as in uterus, cervix and ovaries of females on comparison with untreated control animals both immediately after study termination and after a four week recovery period, respectively, thereby revealing no adverse effects on male and female reproductive organs (Dodd et al. 1986, Union Carbide Corp. Bushy Run Research Center 1985). In males one/10 control animals of the recovery group was diagnosed with epididymitis while in females of the recovery group ovarial cysts ("cystic ovarian bursa") were found in 2/10 animals of the control group but none in the treated groups. One/10 animals each of the control and intermediate dose group (300 ppm) had changes in uterus size ("luminal ectasia") while 1/10 animals of the intermediate dose group (300 ppm) had size changes in the cervix ("luminal ectasia").

In addition, a study conducted to test the genotoxicity of the material on germ cells in a mouse spermatogonia drinking water assay clearly demonstrated the absence of substance associated adverse effects on murine germ cells at a dose close to the MTD supporting observations made on the non-adverse effects of the material to rat testes in repeated dose inhalation studies (RCC-CCR 2000) [modified from OECD SIDS Dossier].

 


Short description of key information:
Based on the overall findings made in a 14 weeks inhalation study the NOEC and LOAEC were 100 and 650 ppm, respectively. The NOAEC for effects on gonadal tissues was 650 ppm.

Effects on developmental toxicity

Description of key information
2,4-pentanedione showed no teratogenic activity. Fetotoxic effects (reduced fetal weights in male fetuses) were observed at 200 ppm without signs of maternal toxicity. In addition, at 400 ppm (reduced fetal weights in fetuses of both sexes and reduced fetal ossification) reduced maternal weight also occurs.
Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
209 mg/m³
Additional information

25 timed-pregnant F344 rats per dose group were exposed to nominal concentrations of 0, 50, 200 and 400 ppm (corresponding to 0; 209; 834 and 1668 mg/m3) of 2,4-pentanedione vapour, respectively, through organogenesis (gestation days 6-15) to evaluate the embryotoxic, fetotoxic and teratogenic potential of the test material. Chamber concentrations of test substance were metered on a regular basis throughout the study. To produce a sufficient number of gravid females untreated male and female rats were mated in a 1:1 fashion. Dams were examined for body weight, liver and thymus weights, gravid uterine weight, status of implantation sites (i.e. resorptions, dead and live fetuses) and maternal brains were examined histopathologically. Live fetuses were removed from the uterus, counted, weighed, sexed and evaluated for external abnormalities. Visceral abnormalities, craniofacial malformations and skeletal defects were examined in exposed as well as in control animals. Apart from a significantly reduced body weight gain in the 400 ppm exposure group (transient reduced body weight on gestation days 9, 12, 15 and 18 but not on gestation day 21, and reduced weight gain for the intervals gestation days 6-9, 6-12, 6-15 (exposure period) and gestation days 6- 18, but not for the postexposure period on gestation days 15-21) no treatment related effects on body weights, liver weights, thymus weights and gravid uterine weights were observable in any dose group at the time of sacrifice as was histopathological examination of the brains. No substance related effects on the number of corpora lutea, on total, non-viable and viable implantations per litter, pre- or postimplantation loss or sex ratio was detectable. Also, there were no maternal deaths, early deliveries or abortions. Fetotoxicity was manifested by reduced fetal weights in both sexes (approximately 10 %) and a consistent pattern of reduced fetal ossification at 400 ppm and by reduced fetal weights in male fetuses at 200 ppm (approximately 3 %), respectively. There was no evidence of embryotoxicity and the incidences of variations by category (external, visceral including craniofacial, and skeletal) or of total variations as well as incidences of external, visceral and skeletal malformations did not differ among groups including those producing maternal toxicity. Based on a significantly reduced body weight gain in the 400 ppm exposure group the NOAEC/LOAEC derived for maternal toxicity is 200 and 400 ppm (= 834 / 1,668 mg/m3 = 288.2 / 576.4 mg/kg bw/d assuming a respiratory minute volume of 0.24 l/min and an average weight of 250 g/rat), respectively. The NOAEC for developmental toxicity is 50 ppm (= 209 mg/m3 = 72.2 mg/kg bw/d), respectively, which is based on reduced fetal weights in male fetuses at 200 and in male and female fetuses at 400 ppm and a consistent pattern of reduced fetal ossification at 400 ppm. [modified from OECD SIDS Dossier]

 

Justification for classification or non-classification

There is no reproductive toxicity study, however the investigations of the reproductive organs of a 14-week inhalation study in rats did not show any effects. Concerning effects on germ cells a dominant lethal assay showed slight but not clear effects on fertility parameters in the (untreated) pregnant females mated with substance treated males being exposed via the inhalation pathway. In an in vivo mouse spermatogonia assay 2,4-pentanedione did not produce chromosomal aberrations after oral administration to male mice at a dose close to the maximal tolerated dose. Minimal fetotoxic effects (reduced fetal weights <5% in male fetuses) were observed at 200 ppm without signs of maternal toxicity. At 400 ppm (reduced fetal weights in fetuses of both sexes and reduced fetal ossification) reduced maternal weight also occurs. It is concluded that maternal toxicity is the major driver for fetotoxicity.