Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
2.21 mg/m³
Most sensitive endpoint:
carcinogenicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: Cox regression (see endpoint summary for details)
Overall assessment factor (AF):
1
Explanation for the modification of the dose descriptor starting point:
no route-to-route extrapolation necessary
AF for dose response relationship:
1
Justification:
accounted for in the model
AF for differences in duration of exposure:
1
Justification:
accounted for in the model
AF for interspecies differences (allometric scaling):
1
Justification:
model derived from human epidemiology studies
AF for other interspecies differences:
1
Justification:
model derived from human epidemiology studies
AF for intraspecies differences:
1
Justification:
accounted for in the model
AF for the quality of the whole database:
1
Justification:
database is robust
AF for remaining uncertainties:
1
Justification:
no unremaining uncertainties
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 DNEL for acute effects should be derived if an acute hazard leading to acute toxicity (eg. C&L) has been identified and there is a potential for high peak exposures. This is not the case with 1,3-butadiene.

 

The DMEL for long term systemic effects was selected from the most sensitive endpoint (carcinogenicity). DNELs for repeat-dose toxicity (inhalation exposure) and reproductive toxicity (developmental toxicity) were 371 mg/m3 and 15 mg/m3 respectively. The DMEL of 2.21 mg/m3 for carcinogenicity is equivalent to 1 ppm. No long-term local effects have been reported.

 

In experimental animals, there is a marked species difference in carcinogenicity (EU RAR 2002). In the mouse, 1,3-butadiene is a potent multi-organ carcinogen. Tumours develop after short durations of exposure, at low exposure concentrations and the carcinogenic response includes rare types of tumours (NTP 1993). In the rat, fewer tumour types, mostly benign, develop at exposure concentrations of 100 to1000-times higher (Owen et al 1987). In humans a positive association was demonstrated between workplace exposure to butadiene for men employed in the styrene-butadiene rubber industry and lymphohaematopoietic cancer (leukemia) (Sathiakumar et al 2005, Graff et al 2005, Delzell et al 2006, Cheng et al 2007, Sielken et al 2006, 2007 & 2008, Sielken and Valdez-Flores 2013).

 

The association between 1,3-butadiene exposure and leukemia has been extensively modeled. The excess risk of leukemia as a result of exposure to 1,3-butadiene has then been determined from these models. The details of this approach can be found in the Summary and Discussion of Carcinogenicity Section. The preferred model for workers is the Cox continuous model adjusted only for age (Cheng et al, 2007)based on all leukemias combined, using the exposure metric that excluded exposure that occurred more than 40 yearsago. This model incorporates dose descriptors and assessment factors and therefore further corrected dose descriptors and overall assessment factors are not required. Risk estimates were calculated using mortality rates and lifetables for 2008-10 for the 28 states of the EU. The estimate of the excess risk of death from leukemia as a result of exposure to a DMEL of 2.21 mg/m3(1 ppm) is 0.39 x 10-4.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
0.265 mg/m³
Most sensitive endpoint:
carcinogenicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: Cox regression (see endpoint summary for details)
Overall assessment factor (AF):
1
Explanation for the modification of the dose descriptor starting point:
no route-to-route extrapolation necessary
AF for dose response relationship:
1
Justification:
accounted for in the model
AF for differences in duration of exposure:
1
Justification:
accounted for in the model
AF for interspecies differences (allometric scaling):
1
Justification:
model derived from human epidemiology studies
AF for other interspecies differences:
1
Justification:
model derived from human epidemiology studies
AF for intraspecies differences:
1
Justification:
accounted for in the model
AF for the quality of the whole database:
1
Justification:
database is robust
AF for remaining uncertainties:
1
Justification:
no unremaining uncertainties
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 DMEL for acute effects should be derived if an acute hazard leading to acute toxicity (eg. C&L) has been identified and there is a potential for high peak exposures. This is not the case with 1,3-butadiene.

 

The DMEL for long term systemic effects was selected from the most sensitive endpoint (carcinogenicity). DNELs for repeat-dose toxicity (inhalation exposure) and reproductive toxicity (developmental toxicity) were 79 mg/m3and 3 mg/m3 respectively. The DMEL of 0.2652 mg/m3 for carcinogenicity is equivalent to 120 ppb. No long-term local effects have been reported.

In experimental animals, there is a marked species difference in carcinogenicity (EU RAR 2002). In the mouse, 1,3-butadiene is a potent multi-organ carcinogen. Tumours develop after short durations of exposure, at low exposure concentrations and the carcinogenic response includes rare types of tumours (NTP 1993). In the rat, fewer tumour types, mostly benign, develop at exposure concentrations of 100 to1000-times higher (Owen et al 1987). In humans a positive association was demonstrated between workplace exposure to butadiene for men employed in the styrene-butadiene rubber industry and lymphohaematopoietic cancer (leukemia) (Sathiakumar et al 2005, Graff et al 2005, Delzell et al 2006, Cheng et al 2007, Sielken et al 2006, 2007 & 2008).

 

The association between 1,3-butadiene exposure and leukemia has been extensively modeled. The excess risk of leukemia as a result of exposure to 1,3-butadiene has then been determined from these models. The details of this approach can be found in the Summary and Discussion of Carcinogenicity Section. The preferred model for the general population is one used for occupational exposure calculations i.e. the Cox continuous model adjusted only for age (Cheng et al, 2007)based on all leukemias combined, using the exposure metric that excluded exposure that occurred more than 40 years ago. The model incorporates dose descriptors and assessment factors and therefore further corrected dose descriptors and overall assessment factors are not required. Instead, an estimate of the concentration of 1,3-butadiene giving an excess risk of death from leukemia (all cell types combined) of 1 in 105was determined and while a higher value could have been proposed by including BD HITS, a DMEL of 120 ppb (0.265 mg/m3) is proposed.