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Key value for chemical safety assessment

Effects on fertility

Description of key information
There are no further data on members of the C4 low 1,3-butadiene category category.
Effect on fertility: via inhalation route
Dose descriptor:
NOAEC
7 131 mg/m³
Additional information

There are no specific studies on the reproductive toxicity of the streams in the C4 low 1,3-butadiene category (CAS Numbers; 91052-98-1, 92045-23-3, 95465-89-7, 95465-90-0 and 95465-91-1) but data are available on the component substances. There are no 2-generation reproduction studies available but there is sufficient weight of evidence from the component substances to conclude that the potential of the members of this category for effects on fertility is low and therefore further testing is scientifically unjustified (Annex XI adaptation). Classification for reproductive toxicity is therefore not warranted.

 

Specific data are as follows:

 

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 combined repeated-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:
There are no specific studies on the streams in the C4 low 1,3-butadiene category (CAS Numbers; 91052-98-1, 92045-23-3, 95465-89-7, 95465-90-0 and 95465-91-1) but data on the component substances ( butane, isobutene and butene isomers) indicate that members of this category have low potential for reproductive toxicity (including effects on fertility). There are no 2-generation reproduction studies available but there is sufficient weight of evidence from the component substances to conclude that further testing is scientifically unjustified (Annex XI 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 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
There are no specific studies on the streams in the C4 low 1,3-butadiene category (CAS Numbers; 91052-98-1, 92045-23-3, 95465-89-7, 95465-90-0 and 95465-91-1) but data on the component substances (butane, isobutene and butene isomers) indicate that members of this category have low potential for developmental toxicity. A developmental toxicity study conducted in rats on 2-methylpropene (butene isomer) produced no treatment-related developmental toxicity. In addition, a weight of evidence evaluation of reproductive toxicity studies indicates that butane, isobutane, 1-butene and 2-butene are not developmental toxins. The NOAEC for developmental toxicity is 8000 ppm (18,359 mg/m3)  based on the study on 2-methylpropene.
Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
18 359 mg/m³
Additional information

There are no specific studies on the developmental toxicity of the streams in the C4 low 1,3-butadiene category (CAS Numbers; 91052-98-1, 92045-23-3, 95465-89-7, 95465-90-0 and 95465-91-1) but data are available on the component substances. There is sufficient weight of evidence from the component substances to conclude that the potential of members of this category for effects on developmental toxicity is low. Classification for developmental toxicity is therefore not warranted.

 

 

Specific data are as follows:

 

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).

 

 

There are no reliable data on the effects of butane, isobutane and the butene isomers on developmental toxicity in humans.

Toxicity to reproduction: other studies

Additional information

There are no other studies, in addition to those described above, on the reproductive or developmental toxicity of members of theC4 low 1,3-butadiene category. 

Justification for classification or non-classification

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