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Key value for chemical safety assessment

Effects on fertility

Description of key information
No other studies are available 
Additional information

Reproductive toxicity data are available for one category stream member, the C2-C4 alkanes and propene.

 

Members and constituents of the Other Petroleum Gases category are flammable gases at room temperature and therefore exposure via the dermal or oral routes is unlikely and the requirement to test is waived in accordance with REACH Annex XI.

 

Liquefied Petroleum Gas

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.

 

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 C1- 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).

 

Propene CAS Number 115-07-1

Overall, there is a considerable amount of data from well conducted and reported guideline studies with adequate and reliable coverage of key parameters for the assessment of the reproductive toxicity potential of propene. A weight of evidence evaluation for propene and its proximate metabolite, propene oxide indicate that there is no evidence for adverse reproductive effects (including fertility). Findings include; no effects in reproductive tissues in repeated dose studies of up to 2 years on propene (NTP, 1985), no reproduction effects in a reproduction screening study (OECD 422) with propene oxide (Okuda, 2006) and no reproduction effects in a 2-generation reproduction study (OECD 416) with propene oxide (Hayes, 1988).

 

 

Summary

No quantitative data were located on the effects on fertility and reproductive parameters of Other Petroleum Gases in humans. 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). Inhalation exposure is the most relevant route, and a GLP-compliant guideline study is available on one category stream, the major components being propane and propylene (93.513%). In a 90 day study on liquefied petroleum gas, 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.

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.

 

A more extensive database exists for main component propene which similarly supports a conclusion of low potential for reproductive toxicity/fertility effects.


Short description of key information:
The weight of evidence from studies on one category stream member and main components C2-C4 alkanes and propene indicates no evidence of reproductive toxicity.

Effects on developmental toxicity

Description of key information
The weight of evidence from studies on liquefied petroleum gas, main components C1-C4 alkanes and propene indicates no evidence of development toxicity. However, category stream members may contain carbon monoxide which could trigger classification for developmental effects.
Additional information

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

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.

 

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).

 

Propene CAS Number 115-07-1

No developmental toxicity was reported when propene was tested in a rat developmental toxicity study (OECD Guideline 414) by inhalational exposure (BASF, 2002). No maternal toxicity was expressed at any concentration up to 10,000 ppm (17,200 mg/m3). There were no treatment-related influences on the gestational parameters and no signs of prenatal developmental toxicity, in particular no indications of teratogenicity. The NOAEC for prenatal developmental and maternal toxicity from inhalation exposure to propene is 10,000 ppm (17,200 m/m3), half the lower explosive limit.

 

 

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, 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. Current GLP-compliant guideline studies (OECD 422) are also available for C2-C4 alkanes up to 6 weeks in duration; there were no developmental malformations or evidence of foetal toxicity. Also data on the component substance propene further indicate that members of this category have low potential for developmental toxicity. Based on these data, no labelling is warranted.

However, some streams in this category may contain carbon monoxide and data on this material indicates evidence of developmental toxicity:

 

Carbon Monoxide CAS number 630-08-0

(Classification: EU Toxic, T Cat 1 R61; GHS/CLP Category 1A, H360D)

The World Health Organisation published an extensive review of carbon monoxide in 1999 (WHO, 1999, updated 2004). In the human body, it reacts readily with haemoglobin to form carboxyhaemoglobin (COHb). Its toxic effects on humans are due to hypoxia, which becomes evident in organs and tissues with high oxygen consumption such as the brain, the heart, exercising skeletal muscle and the developing foetus. Carbon monoxide readily diffuses crosses the placenta and binds to foetal haemoglobin with a higher affinity than for maternal haemoglobin. Furthermore, the gas is cleared from foetal blood slower than from maternal blood, leading to the accumulation of carbon monoxide which, at steady state, may be up to 10 – 15 % higher than maternal concentrations. WHO state that maternal carbon monoxide exposures of 170–230mg/m3 (150–200 ppm), leading to approximately 15–25% carboxyhaemoglobin, can produce reductions in birth weight, cardiomegaly, delays in behavioural development and disruption in cognitive function.

 

Reference

World Health Organisation, 1999

Environmental Health Criteria 213 (Carbon Monoxide, second edition)

1999, updated 2004

 

 

 

 

Toxicity to reproduction: other studies

Additional information

No other studies are available

Justification for classification or non-classification

The weight of evidence from studies on one stream member, the main components C1-C4 alkanes and propene, indicates there is adequate information available from which to assess the potential of Other Petroleum gases to induce reproductive or developmental effects and to conclude that classification under the DPD (Dir 1999/45/EC) or GHS/CLP is not warranted. However category streams containing carbon monoxide may require classification:

According to DPD (Dir 1999/45/EC), category streams which contain ≥ 0.2% carbon monoxide should be classified Cat 1 Dev R61.

According to GHS/CLP, category streams which contain ≥ 0.3% carbon monoxide should be classified at Cat 1A H360D.