Registration Dossier

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:
DNEL (Derived No Effect Level)
Value:
768.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECETOC, 2003; 2010
Overall assessment factor (AF):
3
Dose descriptor:
NOAEC
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
allometric scaling not necessary for inhalation route as starting point and target
AF for other interspecies differences:
1
Justification:
An analysis of assessment factors conducted by ECETOC (2003, 2010) showed that a standard approach of applying a default AF for any remaining differences is not appropriate since, in the majority of cases, this is adequately covered by the inherent interdependence of the inter- and intra-species assessment factors and taken into account by allometric scaling (see, for instance, ECETOC analysis of information from Calabrese and Gilbert (1993) Reg. Tox. Pharmacol. 17: 44-51). Furthermore, data available for butenes, together with information available for chemically-related structures , do not raise concern for possible differences in effect within or between species. Overall, no factor for remaining differences will therefore be applied.
AF for intraspecies differences:
3
Justification:
There are no data to quantify variability in susceptibility to the effects of exposure to butenes in the human population. However the population exposed in the workplace is highly homogeneous and the health of the work force is typically good (healthy worker effect) while metabolic differences due to genetic polymorphisms do not automatically require an increased assessment factor since compensating mechanisms (including alternative pathways of elimination) are often present (ECETOC, 2003, 2010). Following a review of the distribution of variability in toxicokinetic and toxicodynamic parameters for populations of different ages, genders and disease states, ECETOC concluded that human data (Renwick and Lazarus (1998) Reg. Tox. Pharmacol. 27:3-20 ; Hattis et al. (1999) Risk Anal. 19: 421-431) support the use of an assessment factor of 3 (i.e. the 90th percentile of human toxicokinetic and toxicodynamic variability) to account for intra-species variability present within workers.
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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 DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. C&L) has been identified and there is a potential for high peak exposures. This is not the case with the butenes.

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

 

Exposure of rats to 2-butene 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, or in pregnant female rats exposed for 14 days pre-mating, through mating and gestation to day 19 (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 2-butene should be 5000 ppm (11,474 mg/m3) (RIVM 2007 and amended SIDS report 2007).

 

2-Methylpropene also caused no toxicologically significant changes when rats were exposed to 250, 1000 or 8000ppm (573, 2294 or 18,359 mg/m3) for 13 weeks. 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 in 14 week inhalation studies conducted 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.

 

Carcinogenicity studies on 2-methylpropene were also 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 had no adverse effect on 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 toxicological relevance of these nasal lesions observed at very high exposures are likely to be low but conservatively may be considered adverse for this assessment.

Conclusion

1 -Butene, 2 -butene, and 2 -methylpropene show a similar low degree of local and systemic toxicity in repeated-exposure studies. Therefore, the NOAEC for 2 -methylpropene derived in a 2 year cancer bioassay is considered to represent a suitable starting point for the derivation of a DNEL.

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
Value:
229.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECETOC, 2003; 2010
Overall assessment factor (AF):
5
Dose descriptor:
NOAEC
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
Justification:
An analysis of assessment factors conducted by ECETOC (2003, 2010) showed that a standard approach of applying a default AF for any remaining differences is not appropriate since, in the majority of cases, this is adequately covered by the inherent interdependence of the inter- and intra-species assessment factors and taken into account by allometric scaling (see, for instance, ECETOC analysis of information from Calabrese and Gilbert (1993) Reg. Tox. Pharmacol. 17: 44-51). Furthermore, data available for butenes, together with information available for chemically-related structures , do not raise concern for possible differences in effect within or between species. Overall, no factor for remaining differences will therefore be applied.
AF for intraspecies differences:
5
Justification:
There are no data to quantify variability in susceptibility to the effects of exposure to butenes in the human population. However an analysis of assessment factors conducted by ECETOC (2003, 2010) showed that metabolic differences due to genetic polymorphisms do not to automatically require an increased assessment factor since alternative pathways of elimination are often present. Following a review of the distribution of variability in toxicokinetic and toxicodynamic parameters for populations of different ages, genders and disease states, ECETOC concluded that human data (Renwick and Lazarus (1998) Reg. Tox. Pharmacol. 27:3-20 ; Hattis et al. (1999) Risk Anal. 19: 421-431) support the use of an assessment factor of 5 (i.e. the 95th percentile of human toxicokinetic and toxicodynamic variability) to account for intra-species variability present within the general population.
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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 DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. C&L) has been identified and there is a potential for high peak exposures. This is not the case with the butenes.

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

 

Exposure of rats to 2-butene 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, or in pregnant female rats exposed for 14 days pre-mating, through mating and gestation to day 19 (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 2-butene should be 5000 ppm (11,474 mg/m3) (RIVM 2007 and amended SIDS report 2007).

 

2-Methylpropene also caused no toxicologically significant changes when rats were exposed to 250, 1000 or 8000ppm (573, 2294 or 18,359 mg/m3) for 13 weeks. 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 in 14 week inhalation studies conducted 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.

 

Carcinogenicity studies on 2-methylpropene were also 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 had no adverse effect on 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 toxicological relevance of these nasal lesions observed at very high exposures are likely to be low but conservatively may be considered adverse for this assessment.

Conclusion

1 -Butene, 2 -butene, and 2 -methylpropene show a similar low degree of local and systemic toxicity in repeated-exposure studies. Therefore, the NOAEC for 2 -methylpropene derived in a 2 year cancer bioassay is considered to represent a suitable starting point for the derivation of a DNEL.