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Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via inhalation route
Dose descriptor:
NOAEC
7 131 mg/m³
Additional information

There are no multi-generation studies available on members of the C4 high 1,3-butadiene category (CAS numbers; 68476-52-8, 68477-42-9, 68955-28-2, 87741-01-3, 92045-23-3), however the presence of at least 0.1% w/w1,3-butadiene in all of the streams means that there is no REACH requirement for these reproductive toxicity studies as members of the category are labelled as genotoxic carcinogens and germ cell mutagens (Column 2 adaptation). However, there are some non-human studies which do address the potential of the streams and component substances within the category for effects on fertility. The reproductive toxicity (including fertility) of streams in this category is expected to be low. Non-human data are available on one of the streams and on the component substances. In all cases the reproductive toxicity is low. Classification for reproductive toxicity under Dir 1999/45/EC or GHS/CLP is therefore not warranted. 

 

Specific data are as follows:

 

Streams: Male and female rats were exposed to C4 Crude Butadiene (CAS no. 68476-52-8) by inhalation at levels of 0, 2, 10, or 20 mg/L (6h/day, 7 d/week) for two weeks prior to breeding, during breeding (up to two weeks), and continuing through day 19 of gestation. Pups were maintained until postnatal day 4. There were no treatment-related adverse effects on any measures of reproductive function. Based on these data, the NOAEC for reproductive toxicity was 20 mg/L (20,000 mg/m3), the highest concentration tested (Dow, 2001).

 

1,3-Butadiene: 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.

 

Butane: No effects on mating, fertility, or gestation indices or reproductive performance were observed in an OECD Guideline 422 6-week reproduction screening study in rats on butane by inhalation (HLS 2008). The NOAEC is 9,000 ppm (21,394 mg/m3), the highest concentration tested.

 

Isobutane: There were no effects on mating, gestation indices or pup endpoints (survival, body weight and development up to postnatal day 4) when isobutane was tested in an OECD Guideline 422 combinedrepeated-exposure toxicity, reproduction and neurotoxicity screen (HLS, 2010). Rats were exposed by inhalation for up to 6 weeks to 0, 900, 3,000, or 9,000 ppm isobutane. The NOAEC was 3000 ppm (7131 mg/m3), based on equivocal effects at 9000 ppm (21,394 mg/m3), on both fertility and post-implantation loss.

 

Nine out of 12 female rats exposed to 9000 ppm isobutane became pregnant following successful mating, a difference that was not significantly different from the controls (75% of females became pregnant compared with 100% of controls), and of the 9000 ppm exposed rats that became pregnant a statistically significant increase in post-implantation losses was recorded (1.8 per litter compared to 0.8 in controls). A detailed review of the study report supports the possibility that the lower pregnancy rate may have been a chance occurrence on the basis that the group size was small (12 animals per group) and the percentage of females becoming pregnant was near historical levels (75% compared with a historic range of 87.5-100% with a mean of 93.7% in studies conducted between 2001 and 2002). The mean number of corpora lutea, implantation sites, pre-implantation losses, live pups per litter, pup survival to post-natal day 4, and pup sex ratio were not significantly different, all further evidence that a real effect on fertility is questionable. The limitations of this study should be taken into account when considering the potential hazard posed by isobutane. The weight of evidence from the other C4 gases, where no effects on fertility or reproduction were seen, also supports the likely lack of effect of isobutane.

 

Butene isomers (butenes): A weight of evidence evaluation for butene isomers indicates that they have no effect on fertility. No reproductive toxicity was seen in OECD Guideline 422 (reproduction screening) studies on rats via inhalation exposure for 1-butene (Huntingdon, 2003) or 2-butene (TNO 1992b). There was no evidence of systemic toxicity for 1-butene in the parents. Slight reductions in maternal body weight occurred with 2-butene but these were inconsistent and no other treatment-related changes occurred. 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. Based on these data, the NOAECs for reproductive toxicity were 8000 ppm (18,359 mg/m3) for 1-butene 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 2-methylpropene. These repeat dosing studies included parameters such as sperm analysis, estrus 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 effects of the component substances on fertility in humans.


Short description of key information:
Data are available on one of the streams in this category (All CAS numbers are; 68476-52-8, 68477-42-9, 68955-28-2, 87741-01-3, 92045-23-3) and on the component substances (1,3-butadiene, butane, isobutene and butene isomers) that indicate that the members of this category have low potential for reproductive toxicity (including effects on fertility). There are no 2-generation reproduction studies available on the streams but the presence of at least 0.1% w/w 1,3-butadiene in all of the streams means that the requirement for these studies is waived as members of the category are labelled as genotoxic carcinogens and germ cell mutagens (Column 2 adaptation). No biologically significant treatment-related reproductive toxicity or effects on reproductive endpoints in repeat dosing studies were observed in rats or mice after inhalational exposure to 1,3-butadiene, butane, isobutane, 1-butene, 2-butene and 2-methylpropene. The NOAEC for fertility is 3000 ppm (7131 mg/m³) based on the study on isobutane where equivocal effects on fertility occurred at 9000 ppm (21,394 mg/m3). The limitations of this study, together with the weight of evidence from the other C4 gases support an absence of hazard for effects on fertility.

Effects on developmental toxicity

Description of key information
Data are available on one of the streams in this category (All CAS numbers are; 68476-52-8, 68477-42-9, 68955-28-2, 87741-01-3, 92045-23-3) and on the component substances (1,3-butadiene, butane, isobutene and butene isomers) that indicate that the members of this category have low potential for developmental toxicity in humans. There are no developmental toxicity studies available on the streams but the presence of at least 0.1% w/w 1,3-butadiene in all of the streams means that the requirement for these studies is waived as members of the category are labelled as genotoxic carcinogens and germ cell mutagens (Column 2 adaptation). 1,3-Butadiene caused developmental toxicity in rats and mice, in the presence of maternal toxicity, 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 inhalation route
Dose descriptor:
NOAEC
88 mg/m³
Additional information

There are no developmental toxicity studies available on members of the C4 high 1,3-butadiene category (CAS numbers; 68476-52-8, 68477-42-9, 68955-28-2, 87741-01-3, 92045-23-3), however the presence of at least 0.1% w/w 1,3-butadiene in all of the streams means that there is no REACH requirement for developmental toxicity studies as members of the category are labelled as genotoxic carcinogens and germ cell mutagens (Column 2 adaptation). However, there are some non-human studies which do address the potential of the streams and component substances within the category for effects on developmental toxicity. The developmental toxicity of streams in this category is expected to be low. Data are available on one of the streams and on the component substances. In all cases the developmental toxicity is low and classification under Dir 67/548/EEC or GHS/CLP is not warranted. 

 

Non-human information

 

Specific data are as follows:

 

Streams: Male and female rats were exposed to C4 Crude Butadiene (CAS no. 68476-52-8) by inhalation at levels of 0, 2, 10, or 20 mg/L (6h/day, 7 d/week) for two weeks prior to breeding, during breeding (up to two weeks), and through day 19 of gestation. Pups were killed on postnatal day 4. There was no treatment-related maternal toxicity or effects on developmental toxicity or teratogenicity. Based on these data, the NOAEC for reproductive toxicity was 20 mg/L (20,000 mg/m3), the highest concentration tested (Dow, 2001).

 

1,3-Butadiene: Developmental toxicity occurred in rats and mice, in the presence of maternal toxicity, manifested as foetal defects and retardation in fetal development (HLE 1982, Hackett 1987a&b). 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.

 

Butane: No treatment-related effects on offspring survival (to post natal day 4), pup body weight, or macroscopic effects on pups at post-mortem were observed in an OECD Guideline 422 6-week reproduction screening study in rats on butane by inhalation (HLS 2008). The NOAEC for developmental toxicity is 9,000 ppm (21,394 mg/m3), the highest concentration tested.

 

Isobutane: No treatment-related effects on offspring survival (to post natal day 4), pup body weight, or macroscopic effects on pups at post-mortem were observed in an OECD Guideline 422 6-week reproduction screening study in rats on butane by inhalation (HLS 2010). The NOAEC for developmental toxicity is 9,000 ppm (21,394 mg/m3), the highest concentration tested.

 

Butene isomers (butenes): The butenes are not toxic to development. 2-Methylpropene has been tested in a key rat developmental toxicity study (OECD Guideline 414) by inhalational exposure (CTL 2002). There were no effect on the females during gestation, no effects on the number, growth or survival of the foetuses in utero and no effects on foetal development (determined by visceral and skeletal analysis). A NOAEC of 8000 ppm (18,359 mg/m3) (the highest concentration tested) was established for maternal toxicity and foetal toxicity (CTL 2002). 2-Butene and 1-butene also had no effect on developmental toxicity when tested during the reproductive toxicity element of OECD Guideline 422 studies by inhalation exposure. There were no effects on pup body weight gain or observed during macroscopic examination of pups at post mortem (Huntingdon 2003, TNO 1992b). The NOAEC of 8000 ppm (18,359 mg/m3) for developmental toxicity is based on the NOAEC for 2-methylpropene in the developmental toxicity study (CTL 2002).

 

Human information

 

There are no reliable data on the effects of the component substances on developmental toxicity in humans.

Toxicity to reproduction: other studies

Additional information

No further information

Justification for classification or non-classification

There are sufficient data available to conclude that streams within the C4 high 1,3-butadiene category are not toxic to reproduction and have no effect on fertility or development. Consequently, they do not warrant classification under Dir 1999/45/EC or GHS/CLP.