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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

A derived no effect level (DNEL) for acute toxicity should be derived if an acute hazard leading to acute toxicity has been identified and there is a potential for high peak exposures. This is not the case with the butene isomers.

 

Repeat dosing studies via inhalation exposure are available for but-1-ene, but-2-ene and 2-methylpropene. All studies have shown minimal systemic or target organ toxicity.

 

But-1-ene: Exposure of rats to but-1-ene at concentrations of 500, 2000, 8000 ppm (1147, 4589, 18,359 mg/m3) did not induce systemic toxicity in males or females exposed for a minimum of 28 days or in pregnant female rats exposed for 14 days pre-mating, through mating and gestation to day 19. No treatment-related effects on body weight, clinical chemistry, organ weights or histopathology were found. Neurotoxicity screening also showed no effects on motor activity or functional observation battery. A NOAEC of 8000 ppm (18,359 mg/m3) (the highest dose level) was established (Huntingdon, 2003). 

 

But-2-ene: Exposure of rats to but-2-ene at target concentrations of 2500 or 5000 ppm (5737 or 11,474 mg/m3) did not induce significant systemic toxicity in males and females exposed for 28 days (as part of the repeated-dose study), or in pregnant female rats exposed for 14 days pre-mating, through mating and gestation to day 19 (as part of the reproductive and developmental toxicity screening study) (TNO 1992b). Mean absolute organ weights and relative weights were comparable in all groups. No abnormal, treatment-related macroscopic changes (all groups) or pathological changes (only determined in control and 5000 ppm groups) were observed. The only treatment-related changes were some small decreases in body weights and body weight gains in both sexes at both dose levels and decreased food consumption at 5000 ppm during the first week (premating). Although the authors (TNO 1992b) interpreted the NOAEC as 2500 ppm based on these findings, a reanalysis by RIVM (2007) concluded that as these effects were not dose-related and not consistently present during the study the NOAEC for but-2-ene should be 5000 ppm (11,474 mg/m3) (RIVM 2007 and amended SIDS report 2007).

 

2-Methylpropene: Repeated exposure of rats to 2-methylpropene (250, 1000 or 8000ppm (573, 2294 or 18,359 mg/m3)) for 13 weeks resulted in no toxicologically significant changes being observed. The only clinical change was an elevation in ketone bodies detected in urine at 1000 ppm and 8000 ppm (males), the toxicological significance of this is unknown. The NOAEC was 8000 ppm (18,359 mg/m3) the highest concentration level tested (Hazleton 1982). Similar results were obtained by the NTP (NTP, 1998). F344/N rats and B6C3F1 mice were exposed to 2-methylpropene at concentrations of 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm, (1147, 2294, 4589, 9179, 18,359 mg/m3) for 14 weeks. There were no significant exposure-related toxicologic effects in either species at any dose level. Increased kidney weights in mice; and increased liver and kidney weights and minimal hypertrophy of goblet cells lining the nasopharyngeal ducts in rats, were considered to be non-toxic adaptive responses. The NOAEL for both studies was 8000 ppm (18,359 mg/m3) the highest concentration level tested.

 

In a combined chronic toxicity and carcinogenicity study conducted by the NTP, F344/N rats and B6C3F1 mice were exposed to 2-methylpropene at concentrations of 0, 500, 2,000 or 8,000 ppm, (1147, 4589, 18,359 mg/m3) for 105 weeks (NTP, 1998). The non-neoplastic findings from these studies were confined to effects on nasal tissues. In mice, hyaline degeneration of the olfactory and respiratory epithelium was increased in both sexes. The severities of hyaline degeneration increased with increasing exposure concentration. However, this was considered by the NTP to be a nonspecific adaptive response that was not adverse in affected animals. The NOAEC for toxicity in mice was therefore 8000ppm (18,359 mg/m3). Similar findings were observed in rats although the lesions were more severe. An additional finding in rats was that hypertrophy of goblet cells lining the nasopharyngeal duct was marginally increased with 100% incidence in males at 8000 ppm. The NOAEC for toxicity in the rat study was therefore 2000 ppm (4589 mg/m3), lower than that in mice (OECD SIDS Report for Isobutylene, 2003).

The hyaline degeneration has previously been considered for a conservative hazard assessment, however a recent review by the LOA Information Requirements and Toxicology Working Group (IRTWG) agreed with the original conclusions from the NTP that the effects observed were like non-specific adaptive responses to extended exposure to alkene gases and are not adverse. Consequently, the DNEL has been removed for these substances resulting in butene isomers are not being classified for human health effects.

 

Conclusion

But-1-ene, but-2-ene and 2-methylpropene show a similar low degree of local and systemic toxicity in repeated-exposure studies. Though hyaline degeneration was observed in respiratory and olfactory epithelium of mice administered with 2-methylpropene in a 2-year chronic inhalation toxicity study, it was considered to be a non-specific adaptive response and therefore not toxicologically relevant.

Butene isomers are therefore not classified for repeated-dose effects, and no classification is required according to Regulation (EC) No 1272/2008

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

A derived no effect level (DNEL) for acute toxicity should be derived if an acute hazard leading to acute toxicity has been identified and there is a potential for high peak exposures. This is not the case with the butene isomers.

 

Repeat dosing studies via inhalation exposure are available for but-1-ene, but-2-ene and 2-methylpropene. All studies have shown minimal systemic or target organ toxicity.

 

But-1-ene:Exposure of rats to but-1-ene at concentrations of 500, 2000, 8000 ppm (1147, 4589, 18,359 mg/m3) did not induce systemic toxicity in males or females exposed for a minimum of 28 days or in pregnant female rats exposed for 14 days pre-mating, through mating and gestation to day 19. No treatment-related effects on body weight, clinical chemistry, organ weights or histopathology were found. Neurotoxicity screening also showed no effects on motor activity or functional observation battery. A NOAEC of 8000 ppm (18,359 mg/m3) (the highest dose level) was established (Huntingdon, 2003). 

 

But-2-ene:Exposure of rats to but-2-ene at target concentrations of 2500 or 5000 ppm (5737 or 11,474 mg/m3) did not induce significant systemic toxicity in males and females exposed for 28 days (as part of the repeated-dose study), or in pregnant female rats exposed for 14 days pre-mating, through mating and gestation to day 19 (as part of the reproductive and developmental toxicity screening study) (TNO 1992b). Mean absolute organ weights and relative weights were comparable in all groups. No abnormal, treatment-related macroscopic changes (all groups) or pathological changes (only determined in control and 5000 ppm groups) were observed. The only treatment-related changes were some small decreases in body weights and body weight gains in both sexes at both dose levels and decreased food consumption at 5000 ppm during the first week (premating). Although the authors (TNO 1992b) interpreted the NOAEC as 2500 ppm based on these findings, a reanalysis by RIVM (2007) concluded that as these effects were not dose-related and not consistently present during the study the NOAEC for but-2-ene should be 5000 ppm (11,474 mg/m3) (RIVM 2007 and amended SIDS report 2007).

 

2-Methylpropene:Repeated exposure of rats to 2-methylpropene (250, 1000 or 8000ppm (573, 2294 or 18,359 mg/m3)) for 13 weeks resulted in no toxicologically significant changes being observed. The only clinical change was an elevation in ketone bodies detected in urine at 1000 ppm and 8000 ppm (males), the toxicological significance of this is unknown. The NOAEC was 8000 ppm (18,359 mg/m3) the highest concentration level tested (Hazleton 1982). Similar results were obtained by the NTP (NTP, 1998). F344/N rats and B6C3F1 mice were exposed to 2-methylpropene at concentrations of 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm, (1147, 2294, 4589, 9179, 18,359 mg/m3) for 14 weeks. There were no significant exposure-related toxicologic effects in either species at any dose level. Increased kidney weights in mice; and increased liver and kidney weights and minimal hypertrophy of goblet cells lining the nasopharyngeal ducts in rats, were considered to be non-toxic adaptive responses. The NOAEL for both studies was 8000 ppm (18,359 mg/m3) the highest concentration level tested.

 

In a combined chronic toxicity and carcinogenicity study conducted by the NTP, F344/N rats and B6C3F1 mice were exposed to 2-methylpropene at concentrations of 0, 500, 2,000 or 8,000 ppm, (1147, 4589, 18,359 mg/m3) for 105 weeks (NTP, 1998). The non-neoplastic findings from these studies were confined to effects on nasal tissues. In mice, hyaline degeneration of the olfactory and respiratory epithelium was increased in both sexes. The severities of hyaline degeneration increased with increasing exposure concentration. However, this was considered by the NTP to be a nonspecific adaptive response that was not adverse in affected animals. The NOAEC for toxicity in mice was therefore 8000ppm (18,359 mg/m3). Similar findings were observed in rats although the lesions were more severe. An additional finding in rats was that hypertrophy of goblet cells lining the nasopharyngeal duct was marginally increased with 100% incidence in males at 8000 ppm. The NOAEC for toxicity in the rat study was therefore 2000 ppm (4589 mg/m3), lower than that in mice (OECD SIDS Report for Isobutylene, 2003).

The hyaline degeneration has previously been considered for a conservative hazard assessment, however a recent review by the LOA Information Requirements and Toxicology Working Group (IRTWG) agreed with the original conclusions from the NTP that the effects observed were like non-specific adaptive responses to extended exposure to alkene gases and are not adverse. Consequently, the DNEL has been removed for these substances resulting in butene isomers are not being classified for human health effects.

 

Conclusion

But-1-ene, but-2-ene and 2-methylpropene show a similar low degree of local and systemic toxicity in repeated-exposure studies. Though hyaline degeneration was observed in respiratory and olfactory epithelium of mice administered with 2-methylpropene in a 2-year chronic inhalation toxicity study, it was considered to be a non-specific adaptive response and therefore not toxicologically relevant.

Butene isomers are therefore not classified for repeated-dose effects, and no classification is required according to Regulation (EC) No 1272/2008

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