Registration Dossier

Administrative data

Description of key information

Only one stream of the Other Petroleum Gases category has been tested but this and the main components of the category (C1-C4 alkanes and propene) indicate low sub-chronic toxicity by the inhalation route of exposure, the most relevant route. No significant exposure-related toxicological effects or target organ toxicity have been observed in inhalation studies up to 90 days duration on the C2-C4 alkanes, as well as Liquefied Petroleum Gas, the composition of which is mainly propane and propene. Propene has also been thoroughly tested for repeated exposure toxicity up to very high exposure concentrations in sub-chronic and chronic studies. Overall, only minimal local irritation effects to the nasal cavity (mild rhinitis) were observed and only following chronic lifetime exposure to high doses in rats and mice. The mammalian toxicity effects of this category will be not driven by the content of benzene as the latter is present at levels of <0.3%, however, the category may contain carbon monoxide which could trigger classification. 

Key value for chemical safety assessment

Additional information

Repeat dose toxicity data are available for the main components of this category and Liquefied Petroleum Gas; also data are available on C1-C4 alkane mixtures.

 

Other Petroleum Gases are flammable 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.

 

Non-human studies

Methane CAS Number 74-82-8

No quantitative repeat dose toxicity data are available specifically for methane.

 

Ethane CAS Number 74-84-0

No systemic toxicity (i.e., no affect on survival, haematological or clinical chemistry parameters, food consumption, body weight, organ weight, and histopathology) or neurological effects (as measured by clinical observations, functional observational battery, and motor activity) were observed in a 6-week study to modern guidelines and GLP in which ethane was administered to rats by inhalation. The experimentally defined NOAEC is 16,000 ppm (19678 mg/m3), the highest exposure level tested and 50% of the lower explosive limit (HLS 2010).

 

Propane CAS Number 74-98-6

No neurological, haematological, or clinical chemistry effects were observed in a 6-week study to modern guidelines and GLP in which propane was administered to male and female rats by inhalation. There was no effect of treatment on survival and there were no exposure-related systemic effects or effects on body weight, except the 12000 ppm exposed male animals showed an exposure-related 25% decrease in weight gain during the first week of exposures and this difference persisted for the remainder of the 4 weeks of exposure. The lowest observed adverse effect concentration (LOAEC) in this study is 12,000 ppm (equivalent to 21641 mg/m3), the highest exposure level tested and 50% of the lower explosive limit, based on the reduced bodyweight gain in males. The NOAEC is 4,000 ppm or 7214 mg/m3(HLS 2009).

 

 

Isobutane CAS Number 75-28-5

No systemic toxicity (i.e., no affect on survival, haematological or clinical chemistry parameters, food consumption, body weight, organ weight, and histopathology) or neurological effects (as measured by clinical observations, functional observational battery, and motor activity) were observed in a 6-week study to modern guidelines and GLP in which isobutane was administered to rats by inhalation. The experimentally defined NOAEC is 9,000 ppm (21394 mg/m3), the highest exposure level tested and 50% of the lower explosive limit (HLS 2010).

A 90 day inhalation study on a 50:50 wt% mixture of isobutane:isopentane exposed male and female rats to nominal 1000 and 4500 ppm daily for 13 weeks, with an interim kill after 28 days. There were no deaths and transient clinical signs were considered treatment but were not dose related. There were no treatment related gross lesions or kidney/liver weight changes. The rats were not significantly affected by the exposures and there was no evidence of hydrocarbon-induced nephropathy in either sex at study termination. At the 28 -day interim kill mild, transient treatment-related kidney effects were observed in the male rats, statistically significant at 1000 ppm only, however there was no evidence of a dose response and the effect disappeared by 90 days. The NOAEC for this study was 4458 ppm, the highest dose tested (Aranyi 1986).

 

Butane CAS Number 106-97-8

No systemic toxicity (i.e., no affect on survival, haematological or clinical chemistry parameters, food consumption, body weight, organ weight, and histopathology) or neurological effects (as measured by clinical observations, functional observational battery, and motor activity) were observed in a 6-week study to modern guidelines and GLP in which butane was administered to rats by inhalation. The experimentally defined NOAEC is 9,000 ppm (21394 mg/m3), the highest exposure level tested and 50% of the lower explosive limit (HLS 2008).

A 90 day inhalation study on a 50:50 wt% mixture of n-butane:n-pentane exposed male and female rats to nominal 1000 and 4500 ppm daily for 13 weeks, with an interim kill after 28 days. There were no deaths and transient clinical signs were considered treatment but was not dose related. Statistically significant decreases in body weights of both sexes were observed by test weeks 3 and 4, with the males, but not the females, recovering towards the end of the exposure period. There were no treatment related gross lesions or kidney/liver weight changes. Rats were not significantly affected by the exposures and there was no evidence of hydrocarbon-induced nephropathy in either sex at study termination. At the 28-day interim kill mild, transient treatment-related but not exposure-related kidney effects were observed in the male rats, this effect disappeared by 90 days. The NOAEC for this study is 4489 ppm, the highest dose tested (Aranyi 1986).

 

In a mixture study, male rats were exposed by inhalation to concentrations up to 11.8 mg/L (11800 mg/m3 or 4437 ppm) of a mixture containing 25% (by weight) each of isobutane, n-butane, n-pentane, and isopentane for 6 hours per day, 5 days per week, for 3 weeks. There were no signs of systemic toxicity, no effects on bodyweight, organ weights, haematology or serum chemistry and no treatment-related gross or microscopic lesions. The NOAEC for systemic effects and kidney effects is 11.8 mg/L (11800 mg/m3 or 4437 ppm), the highest dose tested (Halder, 1986).

 

 

Propene CAS Number 115-07-1

Key information for the assessment of the repeat-dose toxicity of propene has been reported in several near-guideline sub-chronic and chronic studies via the inhalation route (NTP, 1985). Propene has been thoroughly tested for repeated exposure toxicity up to very high exposure concentrations (10,000 ppm (17,200mg/m3), half of its lower explosive limit value) in sub-chronic and chronic studies. Overall, only minimal local irritation effects to the nasal cavity were observed and only following chronic lifetime exposure to high doses in rats and mice. The mild classification of the lesion and lack of dose-response relationship is consistent with results of shorter term studies, where nasal effects have not been reported in any studies, including 28 day and 90 day NTP studies on propene.The LOAEC for mild rhinitis, only reported following lifetime exposure, is 5000 ppm (8600 mg/m³) in rats and mice. Although there was no clear dose-response relationship or NOAEL for this effect, the weight of evidence clearly indicates that any irritant properties of propene must be extremely weak.

 

 

Liquefied Petroleum Gases

The major constituents are identified as propane and propene (93.5%).

 

The repeated-dose inhalation toxicity of petroleum gas products in laboratory animals was investigated in a 90 day study to modern guidelines and GLP. Groups of rats were exposed to target concentrations of 0; 1,000; 5,000; or 10,000 ppm liquefied petroleum gas (LPG) for 13 weeks (HLS, 2008). The highest exposure concentration was approximated 50% of the lower explosive limit. There was no treatment-related effect on survival, terminal body weight, food consumption, functional observational battery, motor activity parameters, haematological parameters, clinical chemistry values, macroscopic or microscopic evaluations, or on organ weights at any exposure concentration. A no observed adverse effect concentration (NOAEC) of 10,000 ppm is reported for the repeated-dose toxicity of the LPG tested.

 

 

Human studies

Little quantitative data on Other Petroleum Gases were identified.

In a controlled exposure study, Stewart et al (1977, 1978) exposed adult volunteers to isobutane at 500 ppm (1189 mg/m3) 1, 2 or 8 hours/day, five days/week for 2 weeks. During the investigation, all volunteers were kept under comprehensive medical surveillance which included cardiac and pulmonary responses. Repetitive exposures to isobutane were without any measurable untoward physiological effect.

 

Summary

Simple short chain alkanes (i.e methane, ethane, propane, butane, isobutane) can be considered in a similar manner, inhalation exposure is the most relevant route, and current GLP-compliant guideline study data are available for ethane, propane, butane and isobutane which demonstrate low repeat dose toxicity (up to six weeks in duration). These data are supported by studies up to 90 days in duration on C4-C5 mixtures and a 90 day study on liquefied petroleum gas (LPG, main constituent propane and propene), which gave a no observed adverse effect level (NOAEC) of 10,000 ppm, the maximum dose level tested. A consideration of the data available for the alkene, propene, similarly supports a conclusion of low sub-chronic toxicity.

 

The mammalian toxicity effects of this category will be not driven by the content of benzene as the latter is present at levels of <0.3%.However, Petroleum Gas streams may contain carbon monoxide, levels of which could trigger classification.

 

Carbon Monoxide CAS number 630-08-0

(Classification: EU -Toxic T, R48/23; GHS/CLP - STOT-RE Category 1, H372)

The World Health Organisation published an extensive review of carbon monoxide in 1999 (WHO, 1999, updated 2004). In the human body, the gas 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).Chronic exposure to low concentrations of carbon monoxide may lead to cardiovascular effects, tiredness, lethargy, headaches, nausea, dizziness, personality changes, memory problems, as well as impairment of visual, auditory or cognitive function.

 

Reference

World Health Organisation, 1999

Environmental Health Criteria 213 (Carbon Monoxide, second edition)

1999, updated 2004

 

Justification for classification or non-classification

Members of the Other Petroleum Gases category are flammable gases at room temperature and therefore dermal and oral exposure is unlikely. There is sufficient repeat-dose exposure information to indicate they have low sub-chronic inhalation toxicity and therefore do not warrant classification under DPD (Dir 1999/45/EC) or GHS/CLP.

The mammalian toxicity effects of this category will be not driven by the content of benzene as the latter is present at levels of <0.3% (levels of ≥ 1% ≤ 10% would trigger EUR48/23/24/25; GHS/CLPCat 1 H372).

If present in streams, carbon monoxide is toxic to humans due to its ability to react haemoglobin to form carboxyhaemoglobin (COHb).Consequently category streams that contain carbon monoxide up to a level of 1% should be classified as follows:

 

EU: DPD (Dir 1999/45/EC), streams containing ≥0.5% (but less than 5%) carbon monoxide should be classified as Harmful Xn R48/20.

 

GHS/CLP:No classification triggered if present at less than 1% concentration. 

Streams containing >1% (but <10%) should be classified Cat 2 H373 May cause damage to organs through prolonged or repeated exposure.