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Key value for chemical safety assessment

Effects on fertility

Additional information

No data are available for reproductive toxicity of 1,2 -epoxybutane. No indications of reproductive toxicity were seen in repeated dose toxicity studies, in the dominant lethal test in vivo and in developmental toxicity studies. Therefore, testing for this endpoint is not necessary. Nevertheless, since the test substance shows chemical structural analogy to ethylene oxide, reproduction toxicity data which are available for the latter substance were considered in terms of a read-across. In fact, a reproduction toxicity study is available for ethylene oxide (CAS Nr. 75-21-8). In this one-generation study published by Snellings et al. (1982), the effects of ethylene oxide on the reproduction of Fischer 344 rats following repeated exposure by inhalation was investigated. For this purpose, Fischer 344 rats of both sexes, 3 to 4 weeks of age, were used as the parent generation (F0); each group consisted of 30 males and 30 females. Three groups were whole-body exposed to ethylene oxide vapour at approximately 10, 33 and 100 ppm, corresponding respectively to about 0.018, 0.054 and 0.18 mg/L air. For generation of the vapour, a stainless steel cylinder containing liquid ethylene oxide was heated to ca.35°C, the vapour generated was metered in 4400-liter, stainless steel and glass inhalation chambers. Two control groups similarly maintained were exposed only to room air.Chamber atmospheric concentrations in both the test and control chambers were monitored by a gas chromatograph equipped with a flame ionization detector. Approximately 8 analyses were obtained from each chamber within each 6-hr exposure period.

Exposures were initiated for both sexes after a 2-week quarantine period, for 12 weeks prior to the cohabitation period; exposures were for 6 hr per day, 5 days per week. The exposure regimen during cohabitation was 6 hr per day, 7 days per week. During the cohabitation period, one male was placed with each female. The day of observation of a vaginal plug in the females was designated as day 0 of gestation. After 2 weeks of mating, only the females were further exposed. In fact, the dams were exposed from day 0 through day 19 of gestation. From day 20 of gestation until day 5 post-parturition, exposure was stopped. After day 5 post-parturition, the dams were separated from their pups for approx. 6.75 h per day and exposed again to ethylene oxide vapour for 6 h/day, 7 d/week, through day 21 post-parturition. Thus the complete exposure period was about 14 weeks.

No mortalities were seen in the treated F0 animals of both sexes during the 12 weeks of exposure preceding mating. After mating, no dams died during gestation or lactation periods. No treatment-related effects on body weight gain throughout the 12 weeks of exposure for males or females of any exposure group.

Referring to the reproduction parameters, the fertility indices in the 100 ppm group were lower than in controls whereas there were no statistically significant differences between the remaining treated groups (10 and 33 ppm) and the controls. All of the pregnant females in both control groups had a gestation period of 22 days; in the 100-ppm group 7 of 14 dams had longer gestation periods, with 4 of them having a gestation period of 23 days and 2 of them having a gestation period of 25 or 26 days; for one dam, the duration of gestation was given as undeterminable. All gestation periods in the 33 and 10 ppm groups were similar to control (i.e., 22 days).

There were no statistically significant effects on the survival rate of the F1 generation when evaluated as the ratio of pups born alive to the number of pups born per pregnant female, the ratio of pups alive on day 4 post partum to the number of pups alive on day 0 per pregnant female, or the ratio of pups alive on day 14 or 21 post-parturition to the number of pups alive on day 4 per pregnant female. No statistically significant adverse effects on the body weights of the pups per litter at day 4, 14, or 21 post-parturition were seen.

The mean number of pups born on day 0 post parturition per litter in the 100 ppm group was significantly (p < 0.001) lower than in controls. In fact, the means for the 33 ppm, 10 ppm, as well as for the controls were 9 or 10 pups/litter, whereas, for the 100 ppm group, the mean was 4. Furthermore, the mean number of implantation sites per dam in the 100 ppm group was 6, which is significantly lower than the mean of 10 or 11 for the controls;The mean number of implantation sites/dam in both, the 33 and the 10 ppm group was 11, respectively. The ratio of the number of fetuses born to the number of implantation sites per female was determined for each litter. The mean value of this ratio for the 100 ppm exposure group was statistically significantly lower than the value of either air-control group (57 versus 92 or 100).

Thus, since treatment-related effects were seen at the highest tested concentration of 100 ppm ethylene oxide (i.e., 0.18 mg/L air), the NOAEC for the parental generation with respect to reproduction and fertility was 33 ppm (i.e., 0.054 mg/L air).

For the F1 pups, since treatment-related effects were seen at the highest tested concentration of 100 ppm ethylene oxide (i.e., 0.18 mg/L air), the NOAEC was 33 ppm (i.e., 0.054 mg/L air).


Short description of key information:
No data on the reproductive toxicity of 1,2-epoxybutane are available. However, reproduction toxicity data are available for ethylene oxide (CAS Nr. 75-21-8), which is analogue to 1,2-epoxybutane in terms of chemical structure. Thus, the reproduction data for ethylene oxide were considered for 1,2-epoxybutane as read-accross.
A one-generation study on the effects of ethylene oxide on the reproduction of Fischer 344 rats following exposure by inhalation was conducted and published 1982 by Snelling and coworkers (Tox. Appl. Pharmacol. 63: 382 - 388, 1982). The test conduct was similar to the OECD TG 415 (One-Generation Reproduction Toxicity Study).

Effects on developmental toxicity

Description of key information
Studies for teratology assessment of 1,2-epoxybutane had been conducted by the NIOSH and were reported in NIOSH (1981): Teratologic assessment of butylene oxide, styrene oxide and methyl bromide. NIOSH Publication No. 81-124.
Furthermore and as support, a teratogenicity rat and a rabbit study on ethylene oxide (CAS Nr. 75-21-8) also were considered since this substance is analogue to 1,2-epoxybutane in terms of chemical structure. The rat study was published by Snellings er al ( Tox. Appl. Pharmacol. 64: 476 - 481, 1982) whereas the rabbit study was published by Hackett et al. (NIOSH Contracz No. 210-80-0013, PB 83-258038, 1982).
For all studies mentioned above, the exposure route was the whole body inhalation and the test conduct was in principle similar to the OECD TG 414.
Additional information

NIOSH (1981) reported a little indication of maternal toxicity in rats other than relatively trivial effects on weight gain and a few organ weights. This test was done with rats, given concentrations of 250 and 1000 ppm (i.e, 0.75, 3.0 mg/L air) via inhalation (vapour) for 7 h/d for 5 d/w. No mortality without pregestational exposure. High pregestational exposure caused one death. However, this death was not regarded as substance-related (the surviving animals showed no signs of severe toxicity; no further details are given in the report). Pregestational exposure to 1000 ppm of butylene oxide produced a slight, but statistically significant, reduction in the body weight of the rats relative to the controls at most time periods. The differences were transient and were not statistically significant at the end of the pregestation exposure. By 7 days of gestational exposure, the rats exposed at the high levels were significantly lighter than the controls, and remained lighter throughout the study. No remarkable changes in food consumption were produced by pregestational or gestational exposure of rats. The exposure did not affect liver weights. The exposure did not have a major effect on lung weight. No statistically significant differences in placental weight were detected. Apparently normal corpora lutea were noted in the sections of ovary from each rat. The exposure led to a slightly reduced percentage of sperm-positive rats which were pregnant although no clear dose relationship was seen and the decrease was not statistically significant. The exposure had no statistically significant effect on either the weight or length of the fetuses in rats. Statistically significant differences in the sex ratios were not observed. Pregestational and/or gestational exposure did not have statistically significant effects on any of the measures of reproductive success. Alterations of the nature or incidence of morphologic changes related to exposure were not noted. The NOAEC for maternal toxicity was 1000 ppm (i.e., 3 mg/L air) and the NOAEC for developmental toxicity and teratogenicity also was 1000 ppm (i.e., 3 mg/L air).

As the rat, concentrations of 250 and 1000 ppm (i.e., 0.75, 3.0 mg/L air) were given via the inhalation route (vapour) for 7 h/d for 5 d/w to pregnant rabbits (NIOSH, 1981). Fourteen of 24 (58%) exposed to 1000 ppm died during exposure; a significant increase. Supperative pneumonia was the usual necropsy finding in rabbits which died during exposure. The exposure did not have a major effect on lung weights; kidney weights were unaffected. No statistically significant differences in placental weight were detected. The exposure led to a reduced percentage of sperm-positive rabbits, based on the results at scheduled sacrifice. Although this might be considered to be influenced by preimplantation mortality of does, nine of 13 does in the high group which died prior to scheduled sacrifice were pregnant. This gives an overall fraction of 11/23 or 48%, as compared to the 42% pregnant in the air group. The exposure had no statistically significant effect on either the weight or length of the fetuses. The fetuses of the few (2 and 1, respectively) surviving litters of high dose rabbits were markedly smaller than were those of the control or low dose groups. Statistically significant differences in the sex ratios were not observed. The NOAEC for maternal toxicity was found to be 250 ppm (i.e., 0.75 mg/L air); the NOAEC for teratogenicity was 1000 ppm (i.e., 3 mg/L air).

Referring to ethylene oxide, a developmental and teratology study with rat was reported 1982 by Snellings and coworkers. The test conduct was similar to the OECD TG 414 and the pregnant females were whole body exposed to vapours of the test material 6 hr/day, daily from day 6 to day 15 of gestation; the test concentrations were 10, 33 and 100 ppm, corresponding to 0.018, 0.059 and 0.18 mg/L air, respectively.

No treatment-related adverse effects on appearance or behaviour were observed for the dams exposed to ethylene oxide. One litter of the 33 ppm exposure group was totally resorbed. The value for the mean number of fetuses for all ethylene oxide and air-control groups was eight or nine fetuses per dam, and no dead fetuses were found. There were no significant differences between any ethylene oxide exposure and air-control groups for any of the analyzed parameters associated with preimplantation loss or embryo and fetal resorption. In general, the values of all groups were similar for the number of corpora lutea per dam and the number of implantation sites per dam. Consequently, there were no significant differences calculated for percentage of preimplantation loss per dam. Furthermore, the mean values for the percentages of early, late, or total resorption sites per dam were not significantly different from the values of the air-control groups.

Referring to the fetuses, the only significant effect related to the treatment with ethylene oxide was a depression of body weights for both male and female fetuses in the 100 ppm group. There were no significant differences in crown-to-rump length of either sex, and there were no gross external abnormalities noted in the fetuses of any test or control group. Referring to skeletal abnormalities, the percentage of litters (ratio of the number of affected litters to number pregnant x 100) and percentage of fetuses (ratio of the number of affected fetuses to number fetuses for the exposure group x 100) in the 100 ppm group with distal thoracic vertebral centra variations in ossification were numerically elevated when compared to the control groups; however, there were no statistically significant differences noted. Furthermore, when the data for this alteration were expressed as a percentage of fetuses per litter, there were no significant differences noted between the 100 ppm and control groups. There were no significant differences observed for the incidence of variation in ossification of the sternebrae. Referring to visceral alteration, no conspicuous, treatment-related findings were observed.

Thus, for ethylene oxide tested in rats, the NOAEC for maternal toxicity was 0.18 mg/L air, and the NOAEC for developmental toxicity and teratogenicity was 0.18 mg/L air.

Justification for classification or non-classification

No indications of reproductive toxicity were seen in repeated dose toxicity studies with 1,2 -epoxybutane,in the dominant lethal test in vivo and in developmental toxicity studies. Furthermore, since the test substance shows chemical structural analogy to ethylene oxide, reproduction toxicity data which are available for the latter substance were considered in terms of read across, and also indicated that there is no suspicion for reproductive toxicity. The available studies on developmental toxicity and teratogenicity for 1,2 -epoxybutane (rat and rabbit) and for ethylene oxide as structurally close substance (rat) revealed neither developmental toxicity nor teratogenicity. Thus, a classification or labeling of 1,2 -epoxybutane according to the EU 67/548/EEC Directive and according to GHS is not warranted.