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Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

There is no data available on toxicity to reprodution of "Reaction mass of butane and butene". Below we present an assessment of the data for each of the single components Butene, 2 -methylpropene, butane, isobutane and 1,3 -butadiene which are present in "Reaction mass of butane and butene".

Butene/2-methylpropene:

 

Reproduction toxicity studies (OECD Guideline 422 studies) via inhalation exposure are available for but-1-ene (Huntingdon, 2003) and 2-butene (TNO 1992b). 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, 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 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 (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 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 studies on the effects of the butenes on fertility in humans.

 

In conclusion, the weight of evidence from members of the butenes category indicates that they are not toxic to reproduction, including fertility. The NOAEC of 8000 ppm (18,359 mg/m3) for fertility is based on the NOAEC for but-1-ene in the reproductive study (Huntingdon 2003).

 

Butane/Isobutane:

 

Reproductive toxicity data are available for the C2-C4 alkanes. 

Methane CAS Number 74-82-8

No reproductive toxicity data are available specifically for methane.

 

Ethane CAS Number 74-84-0

HLS (2010) report an OECD Guideline 422 combined repeated-exposure toxicity, reproduction and neurotoxicity screen in rats. No effects on mating, fertility, or gestation indices or reproductive performance were observed in a 6-week study in which 0, 1,600, 5,000, or 16,000 ppm ethane was administered to male and female rats by inhalation. The experimentally defined NOAEC is 16,000 ppm (19678 mg/m3).

 

Propane CAS Number 74-98-6

In male and female rats exposed to 0, 1,200, 4,000, or 12,000 ppm propane by inhalation for 6 weeks (OECD Guideline 422), no effects on mating, fertility, or gestation indices or reproductive performance were observed. The experimentally defined NOAEC is 12,000 ppm (21641 mg/m3) (HLS 2009).

 

Isobutane CAS Number 75-28-5

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 C2 - C4 petroleum gases, where no effects on fertility or reproduction were seen, also supports the likely lack of effect of isobutane.

 

Butane CAS Number 106-97-8

HLS (2008) report an OECD Guideline 422 combined repeated-exposure toxicity, reproduction and neurotoxicity screen in rats. No effects on mating, fertility, or gestation indices or reproductive performance were observed in a 6-week study in which 0, 900, 3,000, or 9,000 ppm butane was administered to male and female rats by inhalation. The experimentally defined NOAEC is 9,000 ppm (21394 mg/m3).

 

 

Petroleum gases, liquefied,

The major constituents are identified as propane and propene.

 

HLS (2009) exposed groups of rats to target concentrations of 0; 1,000; 5,000; or 10,000 ppm liquefied petroleum gas (propane and propylene 93.513%) for 6 hours per day, 5 days per week, for 13 weeks. No treatment-related effect on estrous cycle in females or sperm count, motility, or morphology in males was observed at any exposure concentration. The experimentally defined NOAEC is 10,000 ppm.

 

 

Summary

No quantitative data were located on the effects on fertility and reproductive parameters of Petroleum Gases in humans. Inhalation exposure is the most relevant route, and in a 90 day study on liquefied petroleum gas (major constituents are identified as propane and propene) parameters such as sperm analysis, oestrus cycle analysis and histopathology were included (although mating was not carried out), there were no effects with a no observed adverse effect level (NOAEC) of 10,000 ppm, the maximum dose level tested. Furthermore, GLP-compliant guideline studies (OECD 422) are available in animals for C2 – C4 alkanes up to 6 weeks in duration that indicate members of this category have low potential for reproductive toxicity (including effects on fertility). No biologically significant treatment-related reproductive toxicity or effects on reproductive endpoints in repeat dosing studies were observed in rats after inhalational exposure to butane, isobutane, propane or ethane. 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 C2 - C4 petroleum gases support an absence of hazard for effects on fertility.

 

1,3-butadiene:

 

Non-human information

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. 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, 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. 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 (Bevan 1996). 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 data available on toxicity to reprodution of "Reaction mass of butane and butene". An assessment of the data for each of the single components Butene, 2 -methylpropene, butane, isobutane and 1,3 -butadiene which are present in "Reaction mass of butane and butene" leads to the conclusion that there is no requirement for classification and labeling concerning toxicity to reproduction.

Effects on developmental toxicity

Description of key information
There is no data available on developmental toxicity / teratogenicity of "Reaction mass of butane and butene". An assessment of the data for each of the single components Butene, 2 -methylpropene, butane, isobutane and 1,3 -butadiene which are present in "Reaction mass of butane and butene" leads to the conclusion that there is no requirement for classification and labeling concerning developmental toxicity / teratogenicity.
Additional information

There is no data available on developmental toxicity / teratogenicity of "Reaction mass of butane and butene". Below we present an assessment of the data for each of the single components Butene, 2 -methylpropene, butane, isobutane and 1,3 -butadiene which are present in "Reaction mass of butane and butene".

Butene/2-methylpropene:

Members of the butenes category are not toxic to development. 2-Methylpropene has been tested in a key rat developmental toxicity study (OECD Guideline 414) by inhalational exposure at concentrations of 500, 2000 and 8000 ppm (1147, 4589, 18,359 mg/m3). 2-Methylpropene had no effect on the females during gestation. There were also 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).

The low developmental toxicity of 2-methylpropene is consistent with that of other members of the butene category. 2-Butene and but-1-ene also had no effect on developmental toxicity when tested in OECD Guideline 422 studies by inhalation exposure. Neither of these isomers 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 1992b). The NOAECs for developmental toxicity were 8000 ppm (18,359 mg/m3) for but-1-ene and 5000ppm (11,474 mg/m3) for 2-butene (the highest concentrations tested).

 

There are no data on the developmental toxicity of the butenes in humans.

 

In conclusion, the weight of evidence from members of the butenes category indicates that they are not developmental toxins. 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). 

 

Butane/Isobutane:

 

Human data

Two cases are reported of butane exposure in pregnant women, one accidentally exposed in pregnancy week 27, the other intentionally as a suicide attempt in week 30 (Health Council of the Netherlands, 2004).The first woman gave birth to a child with hydranencephaly, while the second woman gave birth to a child that died after 11 hours with severe encephalomalacia and hypoplastic kidneys. In both cases, the brain effects were not considered to be caused by butane but by intrauterine anoxia. In neither of these cases were estimations of the concentrations inhaled made, also, as the history prior to the exposures is unknown, the relationship of the developmental outcomes to butane exposure this study is highly uncertain.

 

Non human data

Methane CAS Number 74-82-8

No developmental toxicity data are available specifically for methane.

 

Ethane CAS Number 74-84-0

HLS (2010) report an OECD Guideline 422 combined repeated-exposure toxicity, reproduction and neurotoxicity screen in rats. There were no effects on offspring survival (to postnatal day 4), pup body weight, or macroscopic post mortem evaluations in a 6 week study to GLP in which rats were exposed by inhalation prior to mating, during mating, and after mating. The experimentally defined NOAEC is 16,000 ppm (19678 mg/m3), the maximum dose tested.

 

Propane CAS Number 74-98-6

In male and female rats exposed to 0, 1,200, 4,000, or 12,000 ppm propane by inhalation for 6 weeks (OECD Guideline 422), prior to mating, during mating, and after mating, no effects on offspring survival (to post natal day 4), pup body weight, or macroscopic post mortem evaluations were observed. The experimentally defined NOAEC is 12,000 ppm (21641 mg/m3) (HLS 2009).

 

Isobutane CAS Number 75-28-5

HLS (2010) report the findings of an OECD Guideline 422 combined repeated-exposure toxicity, reproduction and neurotoxicity screen in rats exposed up to 6 weeks to 0, 900, 3,000, or 9,000 ppm isobutane by inhalation prior to mating, during mating, and after mating. There were no treatment-related differences in offspring survival (to post natal day 4), pup body weight, or macroscopic post-mortem evaluations. The NOAEC for pup endpoints is 9000 ppm (21394 mg/m3). 

 

Butane CAS Number 106-97-8

HLS (2008) report an OECD Guideline 422 combined repeated-exposure toxicity, reproduction and neurotoxicity screen in rats. No effects on offspring survival (to post natal day 4), pup body weight, or macroscopic post mortem evaluations were observed in a 6-week study in which 0, 900, 3,000, or 9,000 ppm butane was administered to male and female rats by inhalation. The experimentally defined NOAEC is 9,000 ppm (21394 mg/m3).

 

Liquefied Petroleum gas

Liquified petroleum gas (propane and propylene 93.513%) was tested in an OECD Guideline 414 Prenatal Developmental Toxicity Study (HLS 2010). Exposure of pregnant rats to target concentrations of 1000, 5000 or 10,000 ppm liquified petroleum gas by whole-body inhalation on gestation days 6 -19 resulted in no effects of exposure. Therefore, a no observed adverse effect concentration (NOAEC) for maternal toxicity and developmental toxicity of 10,000 ppm was indicated.

 

Summary

No quantitative data were located on the effects on developmental parameters of Petroleum Gases in humans. Limited human data demonstrated birth defects in 2 pregnant women were associated with intrauterine anoxia rather than butane exposure, also as the history prior to the exposures is unknown, the relationship of the developmental outcomes to butane exposure this study is highly uncertain.

In animals modern data (OECD 422) are available for ethane, propane, butane and isobutane up to 6 weeks in duration. There were no developmental malformations or evidence of foetal toxicity up to the highest dose levels tested. A prenatal developmental toxicity study is available on liquified petroleum gas (major components propane and propylene) by whole-body inhalation; a no observed adverse effect concentration (NOAEC) for maternal toxicity and developmental toxicity of 10,000 ppm was indicated.

A consideration of the data available supports a conclusion of low potential for developmental effects.

 

 

1,3-butadien:

 

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.

Justification for classification or non-classification

There is no data available concerning toxicity to reproduction, developmental toxicity and teratogenicity of "Reaction mass of butane and butene". An assessment of the data for each of the single components Butene, 2 -methylpropene, butane, isobutane and 1,3 -butadiene which are present in "Reaction mass of butane and butene" leads to the conclusion that there is no requirement for classification and labeling concerning toxicity to reproduction, developmental toxicity and teratogenicity according to CLP (GHS) or 67/548/EEC.