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Key value for chemical safety assessment

Effects on fertility

Description of key information
No further studies.
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
13 276 mg/m³
Study duration:
subacute
Species:
rat
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Non-human information

There are no multi-generation studies available on 1,3-butadiene and there is no REACH requirement for such reproductive toxicity studies as the substance is a genotoxic carcinogen and germ cell mutagen (Annex IX Column 2 adaptation). However, there are some studies which do address the potential of 1,3-butadiene for effects on fertility.

 

A key reproduction/developmental screening study (OECD Guideline 421 study) on 1,3-butadiene has been carried out in rats (WIL, 2003). Male and female rats were exposed to 1,3-butadiene at target concentrations of 300, 1500 or 6000 ppm (663, 3319 or 13,276 mg/m3) for two weeks prior to mating, during mating and through gestation and lactation. F1 males and females were exposed for 7 days post weaning (pnd 21-27 or 28-34). Signs of toxicity were seen in males and females exposed to 1500 or 6000 ppm but there were no treatment-related effects on gonadal function, mating behaviour, conception, gestation, parturition or lactation. Furthermore, there were no treatment-related effects on the growth or development of the offspring during lactation through to weaning. Reduced body weights of the offspring were observed only following post-weaning exposure to 1500 or 6000 ppm. The NOAEL for reproductive toxicity was 6000 ppm (13,276 mg/m3).

 

In an early (supporting) study (Carpenter et al, 1944) rats, guinea pigs and rabbits were exposed to 1,3-butadiene at concentrations of 600, 2300, and 6700 ppm (1327, 5089 and 14824 mg/m3), 7.5h/day, 6 days/week for 8 months and mated during this time. There was no systemic toxicity and fertility was unaffected although numbers of animals were small.

 

No effect on fertility (mating and pregnancy frequency) was seen in dominant lethal studies in rats or mice (see Section on Genetic Toxicity). The results of the more extensive study of Anderson et al (1998) are described here. Male rats were exposed to 1,3 -butadiene for 10 weeks at 0, 65, 400 and 1250 ppm and male mice were exposed to 1,3-butadiene 4 weeks at 0, 12.5, 65 and 130 ppm for 6h/day, 5 days/week in both cases. Animals were then mated with untreated females. Females were killed prior to parturition and foetuses examined (see Developmental Toxicity Section), numbers of live foetuses, numbers of foetuses with gross malformations, numbers of post-implantation deaths, skeletal malformations and cytogenetic analyses were determined. In mice, there were increases in early foetal deaths at 65 (143mg/m3) and 130 ppm (287 mg/m3) but no increases in late deaths. In rats there were no increases in early or late foetal deaths.This study demonstrated that the mouse was more sensitive than the rat to 1,3-butadiene male-mediated effects on the foetus but there were no effects on male-mediated fertility in either species.

 

Information on the effect of 1,3-butadiene on reproductive organs is also available from repeat dose toxicity and carcinogenicity studies (see relevant Sections). Leydig cell tumours were observed in rats following chronic exposure to 1000 or 8000 ppm (2212 or 17701 mg/m3) Owen 1987). Data from NTP carcinogenicity studies (NTP 1993 and NTP 1984) show that ovarian and testicular atrophy occur in the mouse. Atrophy of the testes occurred at 625 ppm (1382 mg/m3) and above whilst ovarian atrophy was observed at all dose levels (6.25 ppm [13 mg/m3] and above) after 2 years. These changes were also seen in a 13 week mouse study (Bevan1996). The exposure response relationship for ovarian atrophy is unclear as although it developed during the study with NOAELs of 62.5 ppm after 9 months and 6.25 ppm after 15 months, its appearance in the lowest dose group coincided with general senescence of the reproductive system (EU RAR 2002). Survival was reduced in both NTP chronic studies and it is possible that the severity of the gonadal effects was a secondary consequence of severe generalised toxicity (EU RAR 2002). The results of Bevan et al (1996) however, demonstrate that ovarian atrophy occurred at 1000 ppm (2212 mg/m3) in the absence of systemic toxicity although as only a single dose was used, a NOAEC could not be established. The effect of 1,3 -butadiene-induced ovarian atrophy on reproductive function in the mouse is unknown.

The effect of 1,3-butadiene on mouse sperm has been examined by Hackett (1988) and Pacchierotti et al (1998). Adult male mice were exposed to 1,3-butadiene at concentrations of  0, 200, 1000, or 5000 ppm (442, 2212 or 11063 mg/m3) 1,3-butadiene 6 hr/day for 5 consecutive days and sperm head morphology was examined 5 weeks later. There was a concentration-related increase in the percentage of abnormal sperm head morphology in exposed mice, from 21% at 200 ppm to 129% at 5000 ppm (relative to controls), although only the increases at 1000 and 5000 ppm (2212 or 11063 mg/m3) were statistically significant (Hackett, 1988). In the study of Pacchierotti et al (1998), mice were exposed to 1,3-butadiene (130, 500 or 1300 ppm; 287, 1106 or 2876 mg/m3) for 6h/day for 5 days. All mice were then mated with untreated females and effects on sperm determined. Cytotoxic effects on differentiating spermatogonia were shown by a concentration-dependent decrease at ≥130 ppm in round spermatids and a similar decrease of elongated spermatids in testes sampled 7 days later. An incomplete repopulation of the elongated spermatid compartment observed 35 days after exposure to 1300 ppm suggested that, at the highest concentration tested, 1,3-butadiene toxicity extended to stem cells. These studies confirm that 1,3-butadiene causes some toxicity to sperm in the mouse although there was no effect on fertility when these animals were mated with untreated females.

 

Human information

There are no studies on the effect of 1,3-butadiene on fertility in humans.

 

 

Conclusions

There is no evidence that 1,3-butadiene has an adverse effect on fertility in the mouse, rat or other species. Data from dominant lethal assays indicate that it has an adverse effect on germ cells in male mice but not rats. The results from long term toxicity and carcinogenicity studies indicate that the ovary and testes are target organs for 1,3-butadiene toxicity in mice. The sensitivity of the mouse ovary is thought to be due to the high levels of butadiene diepoxide present in 1,3-butadiene-exposed mice. It is not known whether ovarian atrophy in 1,3-butadiene-exposed mice affects reproductive function. However, the rat is considered to be more relevant to humans, and ovarian atrophy is not observed in rats exposed to 1,3-butadiene up to 8,000 ppm (Owen 1987). The more recent study of WIL (2003) supports the conclusion that 1,3-butadiene does not affect fertility in rats and the NOAEC for fertility is 6000 ppm (13,276 mg/m3) based on this key study.

 

 

References

EU RAR (2002). European Union Risk Assessment Report for 1,3-butadiene. Vol. 20. European Chemicals Bureau (http://ecb.jrc.ec.europa.eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/butadienereport019.pdf)

 


Short description of key information:
There is no evidence that 1,3-butadiene has an adverse effect on fertility in the mouse, rat or other species. It has an adverse effect on germ cells in male mice and the ovary and testes are target organs for 1,3-butadiene toxicity in mice but evidence indicates that fertility is unaffected. These effects do not occur in rats and differences in the metabolism of 1,3-butadiene in rats and mice is believed to be responsible for the marked species difference. The available data indicates that humans are similar to rats. 1,3-Butadiene therefore has low potential for reproductive toxicity, including fertility. The recent study of WIL (2003) supports this conclusion and the NOAEC for fertility is 6000 ppm (13,276 mg/m3) based on this key study.

Effects on developmental toxicity

Description of key information
1,3-Butadiene caused developmental toxicity in rats and mice, in the presence of maternal toxicity, manifested as retardation in foetal development. There was no evidence of developmental toxicity in the absence of maternal toxicity. The available evidence indicates that 1,3-butadiene has low potential for developmental toxicity in humans. The NOAEC for developmental toxicity is 40 ppm (88 mg/m3), based on the key study of Hackett (1987b) in mice.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
88 mg/m³
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Non-human information

1,3-Butadiene has been tested in two key rat developmental toxicity tests and one key mouse developmental toxicity test conducted by inhalation exposure.

 

In a study conducted by the NTP, rats were exposed to 1,3-butadiene from days 6-15 of gestation at concentrations of 40, 200 or 1000 ppm (88, 442, 2212 mg/m3) (Hackett 1987a). The NOAEC for maternal toxicity was 200 ppm (442 mg/m3) based on reduced body weights. Exposure to 1,3 -butadiene had no effects on developmental parameters at any dose and the NOAEL for developmental toxicity in the rat was 1000 ppm (2212 mg/m3). In a study conducted by HLE (1984) pregnant rats were exposed to 1,3 -butadiene (200, 1000 and 8000 ppm; 442, 2212 and 17701 mg/m3) from days 6-15 of gestation. Maternal toxicity occurred at all dose levels tested. At 8000 ppm, increased incidences of major foetal defects occurred such as severe wavy ribs. These effects were considered to be indicative of delayed development associated with maternal toxicity. There was no evidence of teratogenicity at the lower exposure levels. The NOAEC for teratogenicity was 1000 ppm (2212 mg/m3).

 

Mice were exposed to 1,3-butadiene in a companion study to the NTP rat study (Hackett 1987b). CD1 mice were exposed from days 6-15 of gestation at concentrations of 40, 200 or 1000 ppm (88, 442 or 2212 mg/m3) 6h/day. 1,3-Butadiene produced significant signs of maternal toxicity (reduced body weight gain) at concentrations of 200 and 1000 ppm 1,3-butadiene. The NOAEC for maternal toxicity was 40 ppm (88 mg/m3). Foetal growth retardation, decreased placental weights, and increased incidences of morphologic variations occurred at 200 and 1000 ppm (increased percentages of supernumerary ribs per litter at 200 ppm, and increased percentages of reduced ossification sites and abnormal sternebrae at 1000 ppm) and were attributed to the maternal toxicity. The original authors described foetotoxicity in male mice at 40 ppm (a non-maternally toxic exposure level) and therefore no NOAEC was established for developmental toxicity. Subsequent re-analyses, however, demonstrated that the original analysis of foetal toxicity was incorrect and established a NOAEC for foetal toxicity of 40 ppm and therefore 40 ppm (88 mg/m3) as the overall NOAEC in this study.

In extended dominant lethal studies where foetuses were examined (Anderson et al 1998), male rats were exposed to 1,3-butadiene for 10 weeks at 0, 65, 400 and 1250 ppm and male mice were exposed to 1,3-butadiene 4 weeks at 0, 12.5, 65 and 130 ppm for 6h/day, 5 days/week. Males were then mated with untreated females that were killed prior to parturition. Effects on fertility are described above. There was a non-significant increase in F1 gross abnormalities at 130 ppm in mice but there were no statistically significant increases in either species.

 

 

Human information

There are no studies on the effect of 1,3-butadiene on developmental toxicity in humans.

 

 

Conclusions

The EU RAR (2002) concludes that 1,3-butadiene caused developmental toxicity in rats and mice, in the presence of maternal toxicity, manifested as retardation in foetal development. There was no evidence of developmental toxicity in the absence of maternal toxicity. The available evidence suggests that these effects are of low concern for human health. The NOAEC for developmental toxicity is 40 ppm (88 mg/m3), based on the key study of Hackett (1987b) in mice.

Toxicity to reproduction: other studies

Additional information

No further studies.

Justification for classification or non-classification

1,3-Butadiene is not toxic to reproduction and has no effect on fertility or development. Consequently, it does not warrant classification under Dir 67/548/EEC or GHS.