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Key value for chemical safety assessment

Effects on fertility

Description of key information
No other studies are available 
Effect on fertility: via inhalation route
Dose descriptor:
NOAEC
7 131 mg/m³
Additional information

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

 

Members of the 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.

 

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. 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 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.


Short description of key information:
The weight of evidence from studies on Petroleum Gases, indicates no evidence of reproductive toxicity.

Effects on developmental toxicity

Description of key information
The weight of evidence from studies on Petroleum Gases indicates no evidence of development toxicity.
Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
19 678 mg/m³
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

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.

Toxicity to reproduction: other studies

Additional information

No other studies are available

Justification for classification or non-classification

There is adequate information available from which to assess the potential of Petroleum Gases to induce reproductive or developmental effects and to conclude that classification under the DSD or CLP is not warranted.