Ethane

Endpoint summary

Description of key information

The LC50 in mice of a mixture of isobutane, butane, and propane is 57.42% (approximately 539,600 ppm).

The LC50 in rats of propane exceeds 800000 ppm (equivalent to 1,442,738 mg/m3 or 1443 mg/L)).

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Non GLP, non-guideline, animal experimental study. Limitations in design and reporting but otherwise adequate for assessment

Qualifier:

no guideline available

Principles of method if other than guideline:

To determine whether a mixture of 3 hydrocarbons is more toxic than each individual component.
Groups of male mice were exposed to a mixture of isobutane, butane, and propane (80.4%, 2.5%, and 17.1%, respectively) in air for 2 hours. Oxygen was added to prevent death from hypoxia.

GLP compliance:

no

Test type:

other: LC50

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): A-46
- Substance type: A hydrocarbon mixture specifically developed for the purpose of substituting for fluorocarbons
- Physical state: gas
- Composition of test material, named A-46, percentage of components: isobutane (31 psig) 80.4%, butane (17 psig) 2.5% and propane (108 psig) 17.1%
- Mixture A-26 (46 psig at 21.1°C) 100%

Species:

mouse

Strain:

CF-1

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Wilmington, Massachusetts, USA
- no further details

ENVIRONMENTAL CONDITIONS
- no data

IN-LIFE DATES
- no data

Route of administration:

inhalation: gas

Type of inhalation exposure:

whole body

Vehicle:

other: no data

Details on inhalation exposure:

No methods in the paper itself, the publication refers to an earlier chapter (see other Aviado 1977 reference):
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Glass chamber
- Exposure chamber volume: 10 L
- Source and rate of air:The gaseous mixture was flushed into the chamber at a rate of 3 L/min

All gaseous mixtures were balanced by adding oxygen (25% of the volume of A-46).

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

120 min

Concentrations:

45, 50, 55, 60, 70 and 75 % v/v

No. of animals per sex per dose:

10 males

Control animals:

no

Details on study design:

Duration of observation period following administration: none

Statistics:

An LC50 and 95% confidence limits were calculated by a probit method

Sex:

male

Dose descriptor:

LC50

Effect level:

57.42 other: %

95% CL:

>= 53.96 - <= 60.88

Exp. duration:

120 min

Remarks on result:

other: mixture material. Regression coefficient 0.9811

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

539 600 ppm

Exp. duration:

120 min

Mortality:

Mortality was 0, 20, 50, 60, 80 and 100% at concentrations of 45, 50, 55, 60, 70 and 75%, respectively.

Clinical signs:

other: None reported

Body weight:

None reported

Gross pathology:

n/a

Other findings:

n/a

n/a

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: other: EU (GHS/CLP)

Conclusions:

The 2-hour LC50 in mice of a mixture of isobutane, butane, and propane (80.4%, 2.5%, and 17.1%, respectively) was 57.42% (approximately 539,600 ppm).

Executive summary:

In this study, groups of male mice were exposed to a mixture of isobutane, butane, and propane (80.4%, 2.5%, and 17.1%, respectively) in air for 2 hours to assess the lethality and whether a mixture of 3 hydrocarbons is more toxic than each individual component.

The LC₅₀ of the gas mixture was 57.42% (approximately 539,600 ppm). Mortality was 100% at a concentration of 75%.

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Non guideline, non GLP, animal experimental study, limitations in design but adequate for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

To investigate the concentrations at which central nervous system (CNS) effects occur following inhalation exposure to propane by measurement of the LC50 (15 min) and EC50 (CNS) (10 min) in rats.

GLP compliance:

not specified

Test type:

other: study to investigate the concentrations at which CNS effects occur

Limit test:

no

Specific details on test material used for the study:

Supplier: Imperial Chemical Industries, PLC, Mond Division

Species:

rat

Strain:

other: Alderley Park (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS:
- Rats:
- Source: Alderley Park Breeding Unit, Macclesfield, Cheshire, UK
- Weight at study initiation: 190-230 g

ENVIRONMENTAL CONDITIONS :
n/a

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

other: air

Remark on MMAD/GSD:

n/a

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE:
The gas was passed through a calibrated rotameter and was then mixed with the appropriate quantity of air; the animal was then exposed to the resultant atmosphere. Dynamic atmospheres were generated and gas chromatography was used to measure the concentration of test gas in the atmosphere. As soon as the atmospheric concentration of propane exceeded 25%, oxygen was mixed with the air to maintain a concentration of 20% oxygen.

CHAMBER:
Volume = 500 mL

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gas chromatography

Duration of exposure:

10 - 15 min

Remarks on duration:

n/a

Concentrations:

A range of concentrations was used (0.24% - >80% v/v) such that the no-effect concentration, the 100% effect concentration and several in-between concentrations were determined. Details of the actual concentrations are not provided.

No. of animals per sex per dose:

6 rats

Control animals:

not specified

Details on study design:

Groups of six males or females were used, animals were exposed to the test gas in a 500 mL chamber through which the vapours of test material, mixed with air, were passed. The animals were observed for any effects on the central nervous system, which included stimulation (limb tremor) or depression (ataxia and loss of righting reflex), over a 10 min exposure period. A range of concentrations were used in order to determine both a no-effect concentration, the 100% effect concentration and other concentrations in-between. The EC50 for CNS effect concentration (at 10 min) was calculated, together with the concentration causing mortality after 15 min exposure (LC50 (15 min)).

Statistics:

The EC50, LC50 and 95% confidence intervals were calculated using the moving average interpolation technique of Thompson (1947).

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 800 000 ppm

Exp. duration:

15 min

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

1 442 738 mg/m³ air

Exp. duration:

15 min

Sex:

male/female

Dose descriptor:

LC50

Effect level:

1 443 mg/L air

Exp. duration:

15 min

Sex:

male/female

Dose descriptor:

other: EC50 (CNS)

Effect level:

280 000 ppm

95% CL:

220 000 - 350 000

Exp. duration:

10 min

Mortality:

Death following exposure to propane took the following form associated with a CNS depressant: slight ataxia, loss of righting reflex, loss of movement, narcosis, shallow respiration and death eventually from respiratory depression. Death always occurred during exposure, never afterwards.

Clinical signs:

other: Slight ataxia, loss of righting reflex, loss of movement, narcosis, shallow respiration and due due to respiratory depression.Recovery from a non-lethal exposure was rapid and the rats appeared normal within 10 min with no delayed after effects.

Body weight:

n/a

Gross pathology:

n/a

Other findings:

n/a

n/a

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: other: EU (GHS/CLP)

Conclusions:

The acute inhalation toxicity of propane and its effect on the CNS of experimental rats was determined. The acute inhalation LC50 following 15 minute exposure exceeds 800000 ppm (equivalent to 1,442,738 mg/m3 or 1443 mg/L)). Propane caused depression of the rat CNS after 10 minutes inhalation exposure; EC50 (CNS) 280000 ppm (equivalent to 504,961 mg/m3 or 505 mg/L).

Executive summary:

In this study, the acute inhalation toxicity of propane and its effect on the CNS of experimental rats was determined.

Propane caused depression of the rat CNS after 10 minutes inhalation exposure; EC₅₀(CNS) 280000 ppm (equivalent to 504,961 mg/m3 or 505 mg/L). The acute inhalation LC₅₀following 15 minute exposure exceeded 800000 ppm (equivalent to 1,442,738 mg/m3 or 1443 mg/L). The non-lethal toxic effects were rapidly reversed on cessation of exposure, indicating rapid elimination from the body.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral and dermal toxicity

Members of the Petroleum Gases category are flammable gases at room temperature, indeed most will form explosive mixtures with air, and therefore the requirement for data on acute oral and dermal toxicity is waived in accordance with REACH Annex XI.

 

Acute Inhalation toxicity

Non-human studies

Most of the Petroleum Gases have been tested for acute inhalation toxicity, the studies have been conducted over many years and many are pre-guideline. However, they are adequate for assessment and all LC50 values far exceed 20 mg/L (20,000 mg/m3). Overall there are sufficient data to adequately assess the acute toxicity of the Petroleum Gases.

 

Methane CAS Number 74-82-8

Methane is practically non toxic but acts as a simple asphyxiant at very high concentrations. Brown et al, 1924, demonstrated in cats that a concentration of 87% (606687 mg/m3) caused anaesthesia, whilst 90% (627,607 mg/m3) caused respiratory toxicity and death.

 

Ethane CAS Number 74-84-0

No quantitative acute toxicity data are available for ethane but it is described as a simple asphyxiant.

 

Propane CAS Number 74-98-6

In 1982 Clark et al demonstrated the acute inhalation LC50 following 15 minute exposure to rats exceeds 800000 ppm (equivalent to 1,442,738 mg/m3 or 1443 mg/L). CNS depression occurred after 10 minutes exposure; EC50 (CNS) 280000 ppm (equivalent to 504,961 mg/m3 or 505 mg/L).

Much of the acute inhalation data on propane are from pre-guideline studies. Nevertheless, Cavender (1994) concluded that the gas shows low toxicity in several species. Serious toxicity includes anaesthesia, CNS depression, cardiac sensitisation (all rapidly reversible if exposure ceases) and eventually asphyxia.

 

Isobutane CAS Number 75-28-5

A number of studies indicate that isobutane has low acute inhalation toxicity, as demonstrated by it being designated as Generally Recognised as Safe for its use as a food additive. No toxic effects are noted below its lower flammability limit of 18000ppm (42787 mg/m3, 42.8 mg/L).

The lowest LC50 value in mice (2 hours) of 41% (410,000 ppm (974 mg/L), is reported by Stoughton and Lamson in 1936. Aviado et al 1977 reported the 2 hour LC50 in mice to be slightly higher at 52% (approximately 520,400 ppm or 1237 mg/L), but the same authors also tested a mixture of three hydrocarbons (isobutane, butane, and propane) and found the LC50 of the mixture at 57.42% (approximately 539,600 ppm) to be comparable to isobutane alone.

Both Aviado et al (1977) and Clark et al (1982) demonstrated the range of concentrations required to cause CNS depression/ anaesthesia and those concentrations causing mortality is narrow. There is also evidence of cardiotoxicity including cardiac sensitisation, and decreases in both pulmonary compliance and tidal volume but again at dose levels far exceeding its lower flammability limit.

 

Butane CAS Number 106-97-8

Shugaev et al 1969 reported LC50 values of 658 mg/L in rats and 680 mg/L in mice.

 

Cavender (1994) confirmed that butane has low toxicity for single exposures below the lower flammability limit. Serious toxicity includes anaesthesia, CNS depression and cardiac sensitisation, all rapidly reversible if exposure ceases.

 

 

Human information

Oral and dermal toxicity

No quantitative acute oral or dermal data were identified. However direct skin contact with liquefied material can cause burns and frostbite due to the extreme cold of the liquid.

 

Inhalation toxicity

Little quantitative data on Petroleum Gases were identified. The data suggest that at high concentrations, asphyxiation can occur as a consequence of oxygen deficiency. Symptoms of exposure to high levels of Petroleum Gases include shortness of breath, dizziness, incoordination and confusion but the effects are fully reversible if exposure stops. Simple alkanes like methane and ethane are described as simple asphyxiants but higher molecular weight gases like propane and butane can also cause central nervous depression. Propane, butane and isobutane are considered by the US Food and Drug Administration to be Generally Recognised as Safe (GRAS) when used as propellants, aerating agents and gases and can be used in food products (PHPV 2001).

In a controlled exposure study, Stewart et al (1977, 1978) exposed adult volunteers to isobutane and isobutane/propane mixtures at concentrations of 250-1000 ppm (594 -2377 mg/m3) for 1 min and up to 8 hours. During the investigations, all volunteers were kept under comprehensive medical surveillance which included cardiac and pulmonary responses. No subjective or physiological responses were reported. Likewise, repeat exposures to isobutane at 500 ppm for 1, 2 or 8 hours, 5 days/week for ten exposures were also without any measurable untoward physiological effect. 

 

Fatality data are reported on the higher molecular weight gases like propane and butane where inhalation occurs as a result of intentional misuse. Abuse of gas fuel occurs mainly in teenagers, and Fuke et al (2002), Sugie et al (2004) and Williams and Cole (1998) all report fatalities through exposure to butane gas from cigarette lighters and hair and deodorant sprays. Williams et al 1998 report the acute effects of human solvent abuse include euphoria, disinhibition, hallucinations, ataxia, nausea, convulsions, coma, tinnitus, cardiac arrhythmias, respiratory depression, and even death. Death may ensue by direct cardiac toxicity (arrhythmias) or central nervous system toxicity (respiratory depression) or indirectly by hypoxia, aspiration of vomit or trauma.

The Netherlands Health Council (2004) summarised several individual cases or retrospective studies in which butane was identified as the toxic agent. Again these reports mostly concern its abuse as an inhalant, by adolescents using lighters or hair/deodorant sprays. Butane abuse is often fatal, mostly due to heart failure (arrhythmias, ventricular fibrillation, asystole) and, in one case, due to multiple organ failure involving the central nervous system, cardiovascular and pulmonary systems, and the liver. Of 39 cases where death was considered to be a direct consequence of inhalant abuse, 13 were considered associated with butane. Butane is reported to induce severe acute neurological signs such as seizure, somnolence, coma or cardiovascular complications such as ventricular fibrillation and asystole. Minor symptoms include nausea, dizziness, vomiting, headache, and sore throat.

 

The Netherlands Health Council (2004) also report propane to have CNS depressant and asphyxiating properties. Out of 52 deaths associated with accidental or intentional inhalation of volatile compounds in Virginia (USA) in the period 1987-1996, 6 cases were due to suicide and 7 to accidental overexposure in, usually, the workplace, but the compounds involved were not specified. Of the remaining 39 cases in which death was considered to be a direct consequence of inhalant abuse, 5 were associated with propane.

Berzins (1995) reported on three human inhalation studies on propane. No signs of toxicity or abnormal reactions were observed when eight men and women exposed at 250 and 1000 ppm (0.45 and 1.8 mg/L) for 1 minute to 8 hours. Exposure to 1000 ppm 8 hours/day for 5 consecutive days, and a brief exposure of unknown duration to 10000 ppm (18 mg/mL) did not cause toxicity in humans. Exposure to 100000 ppm (180 mg/L) caused slight dizziness.

 

Assuming a correlation between the anaesthetic potency of a gas and its air/olive oil partition coefficient, Drummond expected that a concentration of propane of 47,000 ppm (86,500 mg/m3) would induce narcosis in man (Drummond 1993, reported by the Netherlands Health Council (2004)).

 

Summary

Members of the Petroleum Gases category are flammable gases at room temperature and therefore the requirement for data on acute oral and dermal toxicity is waived in accordance with REACH Annex XI. Across species, most component gases in this category show low acute inhalation toxicity; indeed, they are practically nontoxic for single exposures below their lower flammability limit, most of which range between 1.8-2.4%, circa 34,000 – 42,000 mg/m3. Asphyxiation (as a consequence of oxygen deficiency) is a potential risk at high dose levels (far exceeding their lower flammability limit) of petroleum gases. Propane and butane can also cause CNS depression. Isobutane and butane are reported to cause cardiac sensitisation and cardiovascular effects (rapidly reversible if exposure ceases). Intentional inhalation of butane can cause euphoria, disinhibition, hallucinations, ataxia, nausea, convulsions, coma, tinnitus, cardiac arrhythmias, respiratory depression, and even death. Death may ensue by direct cardiac toxicity (arrhythmias) or central nervous system toxicity (respiratory depression) or indirectly by hypoxia, aspiration of vomit or trauma.

 

 

Justification for classification or non-classification

Since all Petroleum Gases are gases at room temperature and pressure consideration of oral and dermal toxicity is not considered relevant in this context. In both human and animal studies Petroleum Gases are of low acute toxicity by the inhalation route with LC50 values far exceeding the dose levels which would warrant classification under GHS/CLP.