Buta-1,3-diene

Carcinogenicity

Description of key information

1,3-Butadiene is a multi-species carcinogen. In experimental animals, there is a marked species difference in the carcinogenicity of 1,3-butadiene. 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. In the rat, fewer tumour types, mostly benign develop at exposure concentrations of 100 to1000-times higher than in the mouse. In humans, 1,3-butadiene is a recognised carcinogen. A positive association was demonstrated between workplace exposure to butadiene for men employed in the styrene-butadiene rubber industry and lymphohaematopoietic cancer (leukemia). Various models have established a dose response-relationship for cumulative exposure to 1,3-butadiene, especially concentrations above 100 ppm. The estimates for occupational and population human risk are based on these models.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

2.21 mg/m³

Species:

other: human epidemiology data

Quality of whole database:

Several studies have evaluated the carcinogenicity of 1,3-butadiene in experimental species, both mouse and rat. However, the risk assessment for this substance is driven by epidemiological findings in humans.

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

1,3 -Butadiene is a genotoxic human carcinogen. It therefore warrants classification of Carc.Cat 1: R45 (May cause cancer) under Dir 67/548/EEC and Carcinogenicity Cat1A: H350 (May cause cancer) under GHS/CLP.

Additional information

The carcinogenicity of 1,3-butadiene has been extensively reviewed, including an EU Risk Assessment Report (2002), ECETOC (1997), SCOEL (2007), US EPA (2002) and TCEQ (2008). The non-human data in this endpoint summary is based on the EU RAR (2002) as there have been no new animal data since 2002. The human information has been updated as new information has become available since 2002. The carcinogenicity of 1,3-butadiene in humans is regarded to be the most important health effect of this chemical and the rationale for the development of the worker and population DMELs is described.

 

Non-human information

 

The carcinogenicity of 1,3-butadiene has been studied in rats and mice.

 

In the rat an inhalation study was conducted on behalf of the International Institute of Synthetic Rubber Producers (IISRP) (Owen et al 1987). Groups of male and female rats were exposed to 1,3-butadiene at 1000 or 8000 ppm (2212 or 17701 mg/m³) for 6 hr/day, 5 days/week for 2 years. There were increases in the incidences of pancreatic exocrine adenoma (high dose, male); uterine sarcoma (both doses, female); Zymbal gland carcinoma (high dose, female); mammary tumours (both doses, female); thyroid follicular cell tumours (both doses female) and testis Leydig-cell tumours (high dose). These data suggest that 1,3-butadiene is a weak carcinogen to the rat under the conditions of exposure used in this study. The increased incidence of mainly benign tumours, which occur spontaneously in the rat, suggests that 1,3-butadiene may act by a non-genotoxic mechanism, rather than by a direct effect of reactive metabolites.

 

The US National Toxicology Program has conducted two carcinogenicity studies in mice. In the first (NTP, 1984), male and female B6C3F1mice were exposed to 1,3-butadiene by inhalation at 625 or 1250 ppm (1382 or 2765 mg/m³), 6 hrs day, 5 days per week for 61 weeks. The study was scheduled for 2 years but was stopped earlier because of high mortality in both treated groups. There was clear evidence of multiple organ carcinogenicity for 1,3-butadiene in both sexes, as shown by increased incidences and early induction of haemangiosarcomas of the heart, malignant lymphomas, alveolar/bronchiolar adenomas and carcinomas, and papillomas of the stomach in males and females; and of acinar cell carcinomas of the mammary gland, granulosa cell tumours of the ovary, and hepatocellular adenomas and carcinomas in females. This study demonstrated that 1,3-butadiene is a potent carcinogen in mice causing multi-organ tumours that develop after only 1 year.

 

The second study extended the dose range of the first and also included a “Stop-Exposure” study where mice were exposed for a period then left untreated (NTP 1993). Survival in treated groups was reduced in both standard and “Stop-Exposure” studies due to the presence of malignant neoplasms. The standard and “Stop-Exposure” studies confirmed the clear evidence of carcinogenicity of 1,3-butadiene in both sexes. In the standard study, male and female B6C3F1mice were exposed to 1,3-butadiene by inhalation at 6.25, 20, 62.5, 200 or 625 ppm (13, 44, 138, 442 or 1382 mg/m³), 6 hrs day, 5 days per week for up to 2 years. Tumours arose at all exposure levels. In males there were increased incidences of neoplasms in the haematopoietic system, heart, lung, forestomach, liver, harderian gland, preputial gland, brain and kidney. In females there were increased incidences of neoplasms in the haematopoietic system, heart, lung, forestomach, liver, harderian gland, ovary and mammary gland. Low incidences of intestinal carcinomas in male mice, Zymbal's gland carcinomas in male and female mice, and renal tubule adenomas and skin sarcomas in female mice may also have been related to administration of 1,3-butadiene. In the “Stop-Exposure” study male B6C3F1 mice were exposed to 1,3-butadiene by inhalation at 200 ppm (443 mg/m³) for 40 weeks, 312 ppm (690 mg/m³) for 52 weeks, 625 ppm (1383 mg/m³) for 13 weeks, or 625 ppm (1383 mg/m³) for 26 weeks. After exposure the mice were then left untreated for the remainder of the 2-year study. Tumours at multiple sites were observed at all dose levels with the first tumours appearing after only 13 weeks of exposure to 650 ppm.

 

These NTP studies (standard and "Stop Exposure") also show that 1,3-butadiene causes multi-site carcinogenicity in mice. Tumours arose at all exposure levels. These data indicate that 1,3-butadiene is a genotoxic carcinogen and the risk of carcinogenicity in mice is high even at low exposure levels (NTP 1984, 1993).

 

A final study in mice was conducted by Bucher (1993). Male and female B6C3F1 mice were exposed to 1,3-butadiene for a single 2-hour period to concentrations of 0, 1000, 5000 or 10,000 ppm (2212, 11063 or 22126 mg/m³). The mice were then held for 2 years without treatment. There were no effects on survival at 2 years, no effects on bodyweight and no increased incidences of neoplastic or non-neoplastic lesions attributed to exposure to 1,3-butadiene. Although this study did not identify any carcinogenic effect associated with an acute exposure to 1,3-butadiene the studies with multiple exposures are more relevant for hazard assessment.

 

In conclusion, there is a marked species difference in the carcinogenicity of 1,3-butadiene in experimental animals. The difference in response is consistent with the in vivo genotoxicity of 1,3-butadiene in mice but not rats. 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. In the rat fewer tumour types, mostly benign develop at exposure concentrations of 100 to1000-times higher than in the mouse. Murine T-cell lymphoma results from the suppression of a subpopulation of interleukin-3-responsive cells and ablation of stem cell factor synergy with colony stimulating factor, which the mouse is particularly sensitive towards. Bone marrow-derived cells from rat and human do not show the same sensitivity as those derived from mouse, and consequently these findings in the mouse are not considered to be relevant to humans (Colagiovanni et al, 1993; Irons et al, 1996, 2000). The tumour response in rats suggests that non-genotoxic, possibly hormonal mechanisms influence the carcinogenicity in this species.

 

 

Human information

 

The European Union Risk Assessment Report (EC, 2002) concluded that there is clear evidence from a study in styrene-butadiene rubber (SBR) workers (Delzell et al., 1995, 1996; Macaluso et al., 1996), that occupational exposure to 1,3-butadiene is associated with an excess of leukaemia. IARC (2008) concluded that there is sufficient evidence in humans for the carcinogenicity of 1,3-butadiene and noted that this conclusion was based primarily on the evidence for a significant exposure–response relationship between exposure to 1,3-butadiene and mortality from leukaemia in an update of the SBR workers study (Sathiakumar et al., 2005; Graff et al., 2005: Delzell et al., 2006). More recently IARC have added a statement that “1,3-butadiene causes cancer of the haematolymphatic organs” to their evaluation of the evidence from human studies (Baan et al., 2009). 

The SBR workers study provides good quality information on the association between exposure to 1,3-butadiene and haematolymphatic cancer (HLC) for a large group of over 16,000 workers with a long period of follow up, and the US EPA (2002) concluded that it provided the best published set of data to evaluate human cancer risk from 1,3-butadiene exposure, although the EU RAR (2002) stated that “overall these modelled data cannot be viewed as of sufficient reliability on which to base an estimate of the dose response relationship for the carcinogenic effect”. However, recent study updates incorporate improved exposure estimates for 1,3-butadiene and estimates for potential confounders, styrene and dimethyldithiocarbamate (DMDTC), were calculated (Macaluso et al. 2004). The improved exposure estimates were validated by Sathiakumar et al. (2007) and Sathiakumar et al. (2019). IARC (2008) discussed evidence for an association between 1,3-butadiene and non-Hodgkin lymphoma which derives from the studies of workers in the monomer industry, and noted that they were unable to determine the strength of the evidence for particular histological subtypes of lymphatic and haematopoietic neoplasms because of changes in coding and diagnostic practices. The study by Divine and Hartman (2001) provides the most reliable information about the association between NHL and 1,3-butadiene exposure in monomer workers, but survival analyses showed no increase in risk with increasing cumulative 1,3-butadiene exposure for NHL and all HLC. Sathiakumar et al (2005) reported that they did not find any clear relation between employment in the SBR industry and other haematolymphatic cancers (besides leukaemia) and reported no excess of deaths from NHL and multiple myeloma. Graff et al. (2005) examined exposure-response trends for the same workers and reported a positive association between 1,3-butadiene and leukaemia that was not explained by exposure to other agents examined, but they did not report similar associations for NHL and multiple myeloma.

Estimates of excess leukaemia risk have been derived using the SBR workers study by various groups (SCOEL, 2007; Sielken et al., 2007, 2008; TCEQ, 2008), but no estimates have been derived for HLC. Given the lack of association with other types of HLC, it seems unlikely that modelling the association between HLC and 1,3-butadiene in the SBR workers would provide better estimates of excess risk than modelling the association between leukaemia and 1,3-butadiene. Cheng et al (2007) used Cox regression procedures to examine the exposure–response relationship between several time-dependent 1,3-butadiene exposure indices and lymphoid neoplasms and myeloid neoplasms in addition to leukaemia. They concluded that evidence of an association between 1,3-butadiene and all lymphoid neoplasms or all myeloid neoplasms is less persuasive than that for all leukaemias. Graff et al. (2005) and Sielken et al. (2008) reported no association between acute myelogenous or monocytic leukaemia (AML) and 1,3-butadiene exposure, indicating that non-AML leukaemia may be a better endpoint than all leukaemia. However, there is limited information available to estimate the number of excess leukaemias of this type and quantitative risk assessment in the SBR workers cohort is based on models using all leukaemia as the endpoint.

 SCOEL (2007) agreed that 1,3-butadiene should be treated as a possible human carcinogen, operating via a genotoxic mechanism. Excess risk entailed in exposure during a working life to various concentrations of 1,3-butadiene was calculated using a “step” approach (Zocchetti et al, 2004) for 23 sets of model parameters taken from Delzell et al. (2001). These dose response analyses for the SBR cohort incorporated the more refined exposure estimates of Macaluso et al. (2004), but not the additional 7 years of follow up of the latest study update. SCOEL estimated that occupational exposure to 1 ppm of 1,3-butadiene for a working life (stated to be 40 years between the ages of 20 and 65, but in fact 45 years of exposure), will cause from 0.0 to 107.8 extra leukaemia deaths per 10,000 workers between the ages 20-85 years. However, 12 of the 23 SCOEL estimates are based on models which ignore exposure to 1,3-butadiene at concentrations either below 100 ppm or above 100 ppm, and are not appropriate for risk assessment. With these 12 models excluded, the estimates for 1,3-butadiene exposure of 1 ppm range up to 15.3 per 10,000 excess deaths. However, the major weakness of the step model is that excess death estimates for low exposures are based on a single relative risk (RR) estimate which may have considerable variability. For example, the model giving the highest valid estimate of excess deaths at 1 ppm also gives the same estimate for all 1,3-butadiene exposures < 2.1 ppm, and these are based on a RR of 1.3 with 95% CI (0.4-4.3). In addition, the SCOEL approach doesn’t give a true range of estimates, especially for low exposures, as they are based on RR from different analyses which are highly correlated.

Sielken et al. (2008) used the SCOEL assumptions about the relevant exposure window and the same life table assumptions about mortality rates and survival probabilities as SCOEL (SCOEL, 2007) to calculate estimates of occupational risk. This report and an earlier report (Sielken et al.,2007) used Poisson and Cox regression models to model the association between 1,3-butadiene exposure and all leukaemias and leukaemia subtypes. Their models included terms for both cumulative 1,3-butadiene exposure and the cumulative number of exposures to 1,3-butadiene concentrations > 100 ppm (the number of High Intensity Tasks [HITs]). Their results show that cumulative 1,3-butadiene HITS is an important predictor of risk with an effect that is independent of cumulative 1,3-butadiene exposure. The EU RAR (2002) had earlier noted that there was some indication that exposures accrued by exposure to 1,3-butadiene peaks may be important in the development of leukaemia, but there was insufficient data to clarify this. It can also be deduced from Graff et al (2005) that there were no leukaemia deaths among 34,152 person years of follow up from SBR workers exposed to 1,3-butadiene but not HITs. Sielken et al. (2008) noted that they considered Cox proportional hazards modelling to be more scientifically appropriate than Poisson regression modelling and Cox regression results are given more weight. They reported that all leukaemia and chronic myeloid leukaemia (CML) were associated with cumulative BD HITs, but not cumulative 1,3-butadiene exposure. Chronic lymphocytic leukaemia (CLL) was associated with cumulative 1,3-butadiene exposure, but not cumulative 1,3-butadiene HITs. Acute myelogenous or monocytic leukaemia (AML) was not associated with either cumulative 1,3-butadiene exposure or cumulative 1,3-butadiene HITs. For 1 ppm exposure and their preferred Cox regression model for leukaemia which adjusted for 1,3-butadiene HITs, Sielken et al (2008) estimated 0.33 extra leukaemia deaths per 10⁴workers. The corresponding estimate from a Poisson regression model that adjusted for 1,3-butadiene HITs was 0.53 extra leukaemia deaths per 10⁴workers. For CLL, the only endpoint significantly associated with cumulative 1,3-butadiene exposure before and after adjustment for 1,3-butadiene HITs, Sielken et al. (2008) derived an estimate of 0.16 extra CLL deaths per 10⁴workers.

Sielken and Valdez-Flores (2013) extended the work of Sielken et al (2008) and used the SCOEL approach to estimate the excess risks due to1,3-butadienein halation for six endpoints: leukaemia, AML, CLL, CML, lymphoid neoplasms, and myeloid neoplasms. They concluded that cumulative 1,3-butadiene HITs and other exposure covariates may be more important predictors than cumulative1,3-butadiene ppm-years alone and noted that all of the 71 leukaemia decedents in the UAB study who were exposed to1,3-butadiene had some1,3-butadiene HITs. None of the 1192 exposed workers without1,3-butadiene HITs had leukaemia mortalities. Sielken and Valdez-Flores (2013) noted that cumulative BD ppm-years was not statistically significantly associated with CML, AML, or myeloid neoplasms or (after any one of eight exposure covariates is included in the modeling) leukemia. Sielken and Valdez-Flores (2013) stated that it may be reasonable to consolidate the information over the six endpoints for risk management purposes because the specific endpoint of concern is uncertain. Their best consolidated risk estimate averaged risk estimates for leukaemia (adjusted for1,3-butadieneHITs), CLL (unadjusted) and lymphoid neoplasms (adjusted for cumulative styrene exposure) and gave an estimate of 0.4 extra deaths per 10⁴workers for an exposure of 1,5 ppm.

Cheng et al. (2007) also modelled the leukaemia data from the SBR workers studies using a range of Cox regression models, and further analyses are included in the TCEQ (2008) report. TCEQ (2008) used life table methods to estimate general population lifetime risk estimates using the model parameters derived from these Cox regression models. These risk estimates are not relevant to an occupational exposure scenario, and the regression coefficients of the models are not directly comparable with those fitted by Sielken et al. (2008) which incorporated the SCOEL assumptions about the relevant exposure window and excluded exposures that occurred 40 or more years ago. Cheng et al. (2007) also fitted Cox regression models using either continuous cumulative 1,3-butadiene exposure restricted to the lower 95% of exposure range, or the mean scored deciles of cumulative 1,3-butadiene exposure. However, Cheng et al (2007) noted that they preferred the estimate of the exposure–response trend that is based on the continuous, untransformed form of the 1,3-butadiene variables and the full range of exposure data, but noted the high potential for distortion of the exposure–response relationship as a result of exposure misclassification.

None of the estimates of excess risk described above were derived using EU mortality rates which are available in the Eurostat database, and most assume 45 years of exposure whereas many European bodies such as DECOS and AGS assume 40 years of exposure. However, there are a wide number of regression models available for different endpoints and various covariates, and life table methods which take into account competing risks e.g. those described by Zocchetti et al (2002) and Goldbohm et al (2006), can be used to calculate better estimates of excess risk for the various models using EU mortality rates available in the Eurostat database. The extensive modelling work that has been done suggests that leukaemia is the most appropriate endpoint, and Cox regression is generally regarded to be superior to Poisson regression because it eliminates the need for confounding variables such as age and exposure to be subdivided into categories and the value (e.g., midpoint, mean, or median) used to represent variable values within a category (Sielken and Valdez-Flores, 2013; Cheng et al, 2007). For the same reason, Cox models are superior to simple regression analyses of relative risks (RR) calculated for different categories of exposure e.g. RR calculated for deciles of cumulative exposure reported by Cheng et al (2007), and which do not allow for covariates to be taken into account. However, such an approach may often be all that is possible because of the lack of modelling data, and it does allows quantitative risk assessment based on epidemiological studies to be conducted in a transparent and reproducible manner. One key feature of the SCOEL approach is that it ignores exposure that occurred 40 years previously. This seems especially appropriate when estimating excess cases of leukaemia resulting from exposure to 1,3-butadiene. Sathiakumar et al (2005) reported that the excess of leukaemia deaths in SBR workers was concentrated in hourly workers during the first 30 years from first exposure (33 observed v 22.8 expected):there was little evidence of an increased risk among hourly workers during the period starting 30 years after first exposure (30 observed v 28.5 expected). It is also generally recognized that latency periods are shorter for haematopoietic cancers than solid cancers. For instance, the UK HSE recently calculated the occupational burden of cancer and assumed a maximum latency of 20 years for all haematopoietic cancers i.e. the risk was related only to exposure in the preceding 20 years.

New estimates of excess risk have been calculated for various Cox regression models using the SCOEL approach using mortality rates and life table available in the Eurostat database for the years 2008-10 and the 28 countries of the EU, and modified to incorporate 40 years of exposure from the age of 20 to 60 years. The estimates of excess risk were calculated for males and females and averaged. Table 20 shows Cox regression coefficients and estimates of excess leukaemia deaths for a selection of models in which the hazard function was either a log linear function of continuous cumulative 1,3-butadiene exposure or a log linear function of the mean scored deciles of cumulative 1,3-butadiene exposure. The Cox regression coefficients reported by Sielken et al (2008) for the continuous model use the exposure metric that excluded exposure that occurred more than 40 years ago. Regression coefficients are shown for models which were fitted with and without 1,3-butadiene HITs as covariate, but the number of HITs is treated differently for the three models (either as categorical for quintiles or deciles of exposure, or as continuous). The results for the two continuous models that only adjust for age are very close irrespective of whether the modelling excluded exposure that occurred more than 40 years ago and suggest that it is not necessary to make this distinction. The only major difference is the high coefficient for the mean scored decile model for cumulative 1,3-butadiene exposure that did not adjust for 1,3-butadiene HITs. A similar effect was also seen for Poisson regression models which were also based on mean scored deciles of cumulative 1,3-butadiene exposure. Sielken et al (2008) reported that the coefficient of the Poisson regression model that did not adjust for 1,3-butadiene HITs (1.76 x 10^-3) was considerably higher than the regression model that did adjust for 1,3-butadiene HITs (3.42 x 10^-4).The high coefficient for the categorical model may reflect the high potential for distortion of the exposure–response relationship as a result of exposure misclassification noted by Cheng et al (2007). A model using continuous exposure data may not be robust if there is substantial exposure misclassification. However, the regression coefficient for a mean scored vigintile model (20 equal exposure categories) reported by Cheng et al (2007) was much closer to the regression coefficient of the continuous model, and robust because of the large numbers of observations in each exposure category. All the models that adjust for 1,3-butadiene HITs give similar risk estimates whether cumulative 1,3-butadiene exposure is treated as a categorical or continuous variable, and the differences are likely due to the different treatment of 1,3-butadiene HITs in the different models. Sielken and Valdez-Flores (2013) demonstrate that cumulative 1,3-butadiene exposure and cumulative number of BD HITs can be reasonably treated as independent and a strong argument can be made for including BD HITs in the model. However, inclusion of BD HITs in the model has a relatively modest effect unless cumulative 1,3-butadiene exposure is treated as a categorical variable in the Cox regression model. 

 

Table20. Values of Maximum Likelihood Estimate of β, standard error (SE) and estimates of excess leukaemia deaths derived using SCOEL approach, EU mortality rates/lifetable (2008-2010) and assuming 1 ppm exposure to 1,3-butadiene from age 20 to age 60.

Model	Covariates
	Age		Age & Number of 1,3-butadiene HITs > 100 ppm
	Source	β±SE (excess leukaemia deaths)	Source	β±SE (excess leukaemia deaths)
Cox log-linear ppm-years continuous^1	Sielken et al.(2008)	2.93E-04 ± 1.05E-04 (0.397 per 10^4)	Sielken et al.(2008) Number of HITs categorical (quintiles)	2.15E-04 ± 1.31E-04  (0.291 per 10^4)
Cox log-linear ppm-years continuous	Cheng et al.(2007)	2.9E-04 ± 1.0E-04(0.393 per 10^4)	Cheng et al.(2007) Number of HITs (continuous)	2.5E-04 ± 1.2E-04 (0.339 per 10^4)
Cox log-linear ppm-years mean-scored deciles	Cheng et al.(2007)	7.5E-04 ± 2.2E-04 (1.023 per 10^4)	TCEQ (2008) Number of HITs categorical (deciles)	2.8E-04 ± 2.4E-04   (0.379 per 10^4)

¹ Modelling performed excluding exposure that occurred > 40 years ago

For occupational exposure, a DMEL of 1 ppm (2.21mg/m³) is proposed. The estimate of excess leukaemia deaths (all cell types combined) based on a simple Cox regression model for continuous cumulative 1,3-butadiene exposure adjusted only for age, and derived using the SCOEL approach with EU mortality rates (2008-10) and a 40 year exposure assumption is 0.39 x 10^-4, and is less than 0.4 x 10^-4, which has been proposed as a future limit for acceptable occupational risk (AGS, 2008). Risk estimates for other Cox regression models for continuous cumulative 1,3-butadiene exposure reported by Sielken et al (2008). Cheng et al (2007) and TCEQ (2008), are generally close to 0.4 x 10^-4, even if based on regression models that do not adjust for 1,3-butadiene HITs, and much lower if they do adjust for 1,3-butadiene HITs. In addition, the risk estimate derived from using CLL the endpoint most strongly related to cumulative 1,3-butadiene exposure, suggests that 1 ppm may be conservative.

With regard to general population exposure, the Cox regression model for leukaemia used to estimate occupational risk was also used to estimate risk for the general population. As for occupational exposure, it was assumed that risk was only related to exposure in the preceding 40 years and mortality rates and life tables for the 28 states of the EU and the period 2008-10 were used. Exposure was assumed to occur from birth and lifetime risk was calculated as exposure was still occurring at age 85 years. Results were calculated for males and females and averaged.As the birth ratio for the EU is ~ 1.06 male to 1 female, added deaths were also calculated assuming this ratio of males to females at birth.

For general population exposure, a DMEL of 0.12 ppm (0.265 mg/m³) is proposed. The estimate of excess leukaemia deaths (all cell types combined) based on a simple Cox regression model for continuous cumulative 1,3-butadiene exposure, adjusted only for age, is 0.995 per 100,000. If a birth ratio of 1.06 male to 1 female is assumed, and the excess number of leukaemia deaths increases slightly to 0.998 per 100,000.

  

Additional references

 

Baan R, Grosse Y, Straif K, Secretan B, El Ghissassi F, Bouvard V, Benbrahim-Tallaa L, Guha N, Freeman C, Galichet L and Cogliano V; WHO International Agency for Research on Cancer Monograph Working Group. (2009). A review of human carcinogens--Part F: chemical agents and related occupations. Lancet Oncol. 10 (12),1143-4.

Committee on Hazardous Substances (AGS). (2008). Guide for the quantification of cancer risk figures after exposure to carcinogenic hazardous substances for establishing limit values at the workplace. 1. Edition. Dortmund: Bundesanstalt für Arbeitsschutz und Arbeitsmedizin. Availablehttp://www.baua.de/cae/servlet/contentblob/717582/publicationFile/48510/Gd34.pdfandhttp://www.baua.de/cae/servlet/contentblob/665100/publicationFile/48349/Announcement-910.pdf

Delzell E, Macaluso M, Sathiakumar NandMatthews R. (2001). Leukemia and exposure to 1,3-butadiene, styrene and dimethyldithiocarbamate among workers in the synthetic rubber industry. Chem Biol Interact, 135-136, 515-34.

Delzell, E, N Sathiakumar, and M Hovinga. (1996). A follow-up study of synthetic rubber workers. Toxicology 113, 182-189.

Delzell, E, N Sathiakumar, and M Macaluso. (1995). A follow-up study of synthetic rubber workers. Final report prepared under contract to International Institute of Synthetic Rubber Producers.

ECETOC (1997). 1,3-Butadiene OEL Criteria document. Special Report No. 12

EU RAR (2002). European Union Risk Assessment Report for 1,3-butadiene. Vol. 20. European Chemicals Bureau (http: //ecb. jrc. ec. europa. eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/butadienereport019. pdf)

International Agency for Research on Cancer (IARC). (2008). IARC Monographs on the evaluation of carcinogenic risks to humans. Volume 97. 1,3-Butadiene, ethylene oxide, and vinyl halides (vinyl fluoride, vinyl chloride and vinyl bromide). Lyon: International Agency for Research on Cancer. pp. 45-185.

Macaluso, M, Larson, R, Delzell, E, Sathiakumar, N, Hovinga, M, Julian, J, Muir, D and Cole, P. (1996) Leukemia and cumulative exposure to butadiene, styrene and benzene among workers in the synthetic rubber industry. Toxicology, 113, 190-202.

Macaluso, M, Larson, R, Lynch, J, Lipton, S and Delzell, E. (2004). Historical estimation of exposure to 1,3-butadiene, styrene, and dimethyldithiocarbamate among synthetic rubber workers. J. Occup. Environ. Hyg. 1, 371-390.

Sathiakumar N, Delzell., Cheng H, Lynch J, Sparks W and Macaluso M. (2007). Validation of 1,3-butadiene exposure estimates for workers at a synthetic rubber plant, Chem. -Biol. Interact. 166, 29–43.

Sathiakumar N, Delzell., Tipre M, Leader M, Brill I. (2019). Mortality among men and women in North American synthetic rubber industry, 1943 to 2009, J Occup Environ Med. 166, 61(11) 887 -897.

SCOEL. (2007). Recommendation from the Scientific Committee on Occupational Exposure Limits: risk assessment for 1,3-butadiene. SCOEL/SUM/75 final (updated Feb 2007).

Texas Commission on Environmental Quality (TCEQ) (2008). Development Support Document. 1,3-Butadiene. Chief Engineer’s Office. Available: http: //tceq. com/assets/public/implementation/tox/dsd/final/butadiene, _1-3-_106-99-0_final. pdf

United States Environmental Protection Agency (USEPA). (2002). Health Assessment of 1,3-Butadiene. EPA/600/P-98/001F. National Center for Environmental Assessment, Office of Research and Development, Washington D. C.

Zocchetti C, Pesatori AC, Bertazzi PA. (2004) [A simple method for risk assessment and its application to 1,3-butadiene]. Med Lav. 95(5), 392-409.

Justification for selection of carcinogenicity via inhalation route endpoint:
Assessment is based on human epidemiology studies, which cannot be linked here. The effect level is the DMEL associated with a cancer risk estimate of 0.393x10-4.

Carcinogenicity: via inhalation route (target organ): cardiovascular / hematological: other