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Key value for chemical safety assessment

Effects on fertility

Description of key information
No further studies.
Effect on fertility: via inhalation route
Dose descriptor:
NOAEC
13 276 mg/m³
Additional information

There are no reproduction studies carried out on 1,2-butadiene itself, however, in accordance with the strategy described in Section 7.1 (Toxicokinetics endpoint summary), reproduction studies in the rat on the structural analogue, 1,3-butadiene, are used for read across and reproduction studies in the mouse and rat on the mono-butene isomers, 1-butene, 2-butene and 2-methylpropene are also used to provide weight of evidence. There is no requirement for a 2 -generation reproduction study as the registration intention under REACH for this substance is between 100-1000 tonnes.

 

A key reproduction/developmental screening study (OECD Guideline 421 study) on buta-1,3-diene 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 NOAEC for reproductive toxicity was 6000 ppm (13,276 mg/m3) (the highest concentration tested.

 

Two supporting reproduction toxicity studies (OECD Guideline 422 studies) have been carried out on mono-butene isomers. Inhalation exposure of rats to but-1-ene and 2-butene produced no effects on reproductive toxicity including fertility. Male and female rats were exposed to the butene isomers for two weeks prior to breeding, during breeding and until day 19 of gestation. The dams were then allowed to deliver their litters, which were retained until post-natal day 4. Target concentrations were: but-1-ene 500, 2000 or 8000 ppm (1147, 4589, 18,359 mg/m3) and 2-butene 2500 or 5000 ppm (5737 or 11,474 mg/m3). There was no evidence of systemic toxicity for but-1-ene in the parents. Slight reductions in maternal body weight occurred with 2-butene. There were no effects on mating behaviour, fertility and gestation indices, the number of implantation sites per dam, numbers of pups delivered, viability of pups at and after birth and the pup sex ratio when compared to the control group (Huntingdon 2003, TNO 1992b). Based on these data, the NOAECs for reproductive toxicity were 8000 ppm (18,359 mg/m3) for but-1-ene and 5000 ppm (11,474 mg/m3), for 2-butene, the highest concentrations tested.

 

In addition, no effects on male and female reproductive parameters in rats and mice were observed in 14 week inhalation exposure studies of the mono-butene isomer, 2-methylpropene. These repeat dosing studies included parameters such as sperm analysis, oestrus cycle analysis and histopathology (although mating was not carried out). NOAECs of 8000 ppm (18,359 mg/m3) for both rat and mouse studies were established (NTP 1998).

 

There are no data on the effect of 1,2-butadiene on fertility in humans.

 

In conclusion, the weight of evidence from 1,3-butadiene and mono-butene isomers indicates that 1,2-butadiene has low potential for reproductive toxicity, including fertility. The NOAEC for fertility is 6000 ppm (13,276 mg/m3), based on the key study for on 1,3-butadiene (WIL 2003).


Short description of key information:
There are no reproduction studies carried out on 1,2-butadiene itself but a weight of evidence evaluation of reproductive toxicity studies and reproductive endpoints in repeat dosing studies with 1,3-butadiene and butene isomers indicates that 1,2-butadiene has low potential for reproductive toxicity, including fertility. The NOAEC for fertility is 6000 ppm (13,276 mg/m3) (the highest dose tested), based on the key study on 1,3-butadiene.

Effects on developmental toxicity

Description of key information
There are no developmental toxicity studies carried out on 1,2-butadiene itself but a weight of evidence evaluation of developmental toxicity studies with 1,3-butadiene and the mono-butene isomer, 2-methylpropene, indicates that 1,2-butadiene has low potential for developmental toxicity. There was no evidence of developmental toxicity at the lower exposure levels where maternal toxicity was not encountered. The NOAEC for developmental toxicity is 1000 ppm (2212 mg/m3), based on two key studies on 1,3-butadiene.
Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
2 212 mg/m³
Additional information

There are no developmental toxicity studies carried out on 1,2-butadiene itself, however, in accordance with the strategy described in Section 7.1 (Toxicokinetics endpoint summary), two key developmental toxicity studies in the rat on the structural isomer, 1,3-butadiene, are used for read across and a supporting developmental toxicity study in the rat on the mono-butene isomer, 2-methylpropene, has been used to provide weight of evidence. 

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 where maternal toxicity was not encountered. The NOAEC for teratogenicity was 1000 ppm (2212 mg/m3).

2-Methylpropene (isobutylene) has been tested in a rat developmental toxicity study (OECD Guideline 414) by inhalational exposure at levels of 500, 2000 and 8000 ppm (1147, 4589, 18,359 mg/m3). 2-Methylpropene had no effect on the number, growth or survival of the foetuses in utero and no effect on foetal development (determined by visceral and skeletal analysis). A NOAEC of 8000 ppm (18,359 mg/m3) was established (CTL 2002). The low developmental toxicity of 2-methylpropene is consistent with that of other members of the butene category. 2-Butene and 1-butene also had no effect on developmental toxicity when tested in OECD Guideline 422 studies by inhalation exposure. Neither of these compounds produced treatment-related effects on the development of pups during the reproductive toxicity element of the studies. There were no effects on pup body weight gain or observed during macroscopic examination of pups at post mortem (Huntingdon 2003, TNO 1992). The NOAECs for developmental toxicity were 8000 ppm (18,359 mg/m3) for 1-butene and 5000ppm (11,474 mg/m3) for 2-butene (the highest concentrations tested).

 

There are no data on the effect of 1,2-butadiene on developmental toxicity in humans.

 

In conclusion, the weight of evidence from 1,3-butadiene and 2-methylpropene indicates that 1,2-butadiene has low potential for developmental toxicity. The NOAEC for developmental toxicity is 1000 ppm (2212 mg/m3), based on the key studies of Hackett (1987) and HLE (1981) on 1,3-butadiene.

Toxicity to reproduction: other studies

Additional information

No further studies.

Justification for classification or non-classification

1,2 -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/CLP.