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Description of key information

1,3-Butadiene is a flammable gas at room temperature and therefore the requirement for data on oral and dermal repeat dose toxicity is waived in accordance with REACH Annex XI. It exhibits marked species differences in repeat dose toxicity studies via inhalation exposure. It has low toxicity in the rat, with minimal effects seen after exposure to 8000 ppm (17,701 mg/m3) for 2 years. No chronic non-neoplastic effects were seen in humans, although data are limited. The mouse is the most sensitive species where the target organs are bone marrow, ovary and testis a NOAEL for repeat dose toxicity in the chronic studies has not been established due to neoplasia-related toxicity. Species differences in metabolism are believed to be responsible for the species-specific toxicity with humans being more similar to rats. The NOAEC for repeat dose toxicity is therefore 1000 ppm (2212 mg/m3) as defined by rat studies.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
2 212 mg/m³
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

1,3-Butadiene is a gas and therefore significant exposure via the dermal or oral routes is unlikely. No studies using these routes are available for 1,3-butadiene. The requirement for data on repeat dose oral and dermal toxicity is waived in accordance with REACH Annex XI, as 1,3-butadiene is a flammable gas at room temperature.  

The repeat dose toxicity of 1,3-butadiene has been extensively reviewed, including an EU Risk Assessment Report (2002), ECETOC (1997), US EPA (2002) and TCEQ (2008). This endpoint summary is based on the EU RAR (2002) and there have been no new reports on the chronic toxicity of 1,3-butadiene since 2002. The studies described here and for which robust summaries have been prepared are the most significant and reliable studies on 1,3-butadiene although other less reliable studies are described in EU RAR (2002).  

Non-Human Information  

In the rat, exposure to 1,3-butadiene results in low toxicity. The most comprehensive information in the rat is available from a carcinogenicity study (Owen et al, 1987). In this key study, male and female rats were exposed to 1,3-butadiene at 0, 1000, or 8000 ppm (2212 and 17701 mg/m3), 5 days/week, for up to 2 years. There were no effects on haematology, blood chemistry, urine analysis and neuromuscular function that were associated with treatment. Non-neoplastic findings were limited to changes in clinical condition, suppression of body weight gain, reduced survival, increased weights of liver, kidney, heart, lung and spleen, nephrosis of the kidney and focal metaplasia in lung. The neoplastic changes are described in the Section on Carcinogenicity. A NOAEC of 1000 ppm (2212 mg/m3) for systemic toxicity was established based on some minimal toxic effects (increased heart weight and kidney nephrosis) occurring at 8000 ppm.  

In other studies in rats, inhalation exposure of rats to 1,3-butadiene at concentrations of 1000, 2000, 4000 and 8000 (2212, 4425, 8850 and 17701 mg/m3) for 13 weeks produced no treatment-related effects except moderately increased salivation. There were no effects on growth rate, food consumption, haematology, clinical chemistry, urine analysis or macroscopic and histopathological effects. In this study the NOAEC for 1,3-butadiene in the rat was 8,000 ppm (17,701 mg/m3) (Crouch et al 1979). Similar results were reported by Bevan et al (1996), where rats were exposed to 1,3-butadiene at a single concentration of 1000 ppm (2212 mg/m3) for 13 weeks. There were no effects other than minor increases in liver and kidney weights in male rats. Hyaline droplet formation was observed in the kidneys of 20% of treated rats but there was no cytotoxicity associated with this. None of the effects were considered to be adverse.  

Other species were investigated by Carpenter et al (1944) and no significant adverse effects were noted. Rats, guinea pigs, rabbits and dogs were exposed to 1,3-butadiene at concentrations of 600, 2300, and 6700 ppm (1327, 5089 and 14824 mg/m3), 7.5h/day, 6 days/week for 8 months. There were no deaths and no effects on body weight, organ weights, urinalyses, micropathology, clinical chemistry or haematology although the numbers of animals were small. At the highest concentration of 6700 ppm (14824 mg/m3) body weight gain was reduced in rats and there was a light cloudy swelling in some livers of rats and rabbits.

Repeated exposure of mice to 1,3-butadiene results in toxicity. The non-neoplastic data from two carcinogenicity studies are available (NTP 1984 and NTP 1993) although poor survival and severe systemic toxicity at concentrations at and above 20 ppm (44 mg/m3) confounds interpretation of these studies. In the first study (NTP, 1984), male and female B6C3F1 mice were exposed to 1,3-butadiene for 2, 14 or 60 weeks at concentrations of 0, 625, 1250, 2500, 5000 and 8000 ppm (1382, 2765, 5531 and 17701 mg/m3), 6 hours/ day, 5 days/ week. Survival was unaffected and no pathologic effects were observed after 2 weeks. After 14 weeks, the survival of male mice exposed to 5,000 or 8,000 ppm 1,3-butadiene was markedly reduced and body weight gain was reduced at 2500 ppm and above. No other compound-related effects were observed at this time and a NOAEC of 1250 ppm (2765 mg/m3) can be established, based on reductions in body weight gain at the higher dose level. After 60 weeks, there was clear evidence of carcinogenicity, as shown by increased incidences of tumours at many sites in both sexes (see Section on Carcinogenicity). Exposure of mice to 1,3-butadiene was primarily associated with tumours of the haematopoietic system. Non-neoplastic effects seen were ovarian and testicular atrophy, congestion, haemorrhage and hyperplasia of the lungs, haemorrhage and necrosis of the liver, thymus and bone marrow atrophy, epithelial hyperplasia of the forestomach and endothelial hyperplasia and mineralisation of the heart. Chronic inflammation and fibrosis developed in the nasal cavities of males. 1,3 -Butadiene therefore caused severe toxicity and survival was reduced due to malignant tumours. A NOAEL could not be identified in this study.

In the second study (NTP, 1993) mice were exposed to 6.25, 20, 62.5, 200 or 625 ppm 1,3-butadiene (13, 44, 138, 442 or 1382 mg/m3), 6 hours/ day, 5 days/ week for up to 2 years. This study is the key study for the repeat dose toxicity of 1,3-butadiene in the mouse due to its length and number of exposure concentrations. Survival was reduced at 20 ppm and above due to malignant neoplasms (primarily lymphocytic lymphoma, see Section on Carcinogenicity). Increased incidences of non-neoplastic lesions in exposed mice included bone marrow atrophy; testicular atrophy; ovarian atrophy, angiectasis, germinal epithelial hyperplasia, and granulosa cell hyperplasia; uterine atrophy; cardiac endothelial hyperplasia and mineralization; alveolar epithelial hyperplasia; forestomach epithelial hyperplasia; and Harderian gland hyperplasia. Ovarian atrophy was observed at all dose levels after 2 years. The exposure response relationship for ovarian atrophy is unclear as although it developed during the study with NOAECs of 62.5 ppm after 9 months and 6.25 ppm after 15 months, its appearance in the lowest dose group coincided with general senescence of the reproductive system. Tumours also arose at all exposure levels and survival was markedly reduced. The EU RAR (2002) states “it is possible that the gonadal effects seen in this study are a secondary consequence of severe generalised toxicity”. No NOAEC could be defined for this study.

Other supporting studies also demonstrated that 1,3-butadiene is toxic to mice in studies from 2-13 weeks duration (NTP 1984, Bevan et al 1996). The bone marrow, ovary and testis are important targets. Bevan et al (1996) exposed male and female mice to 1,3-butadiene at 1000 ppm (2,212 mg/m3), 6 hr/day, 5 days/wk for 13 weeks, treatment-related ovarian atrophy, mild macrocytic anaemia and slight testicular degeneration occurred.

Irons et al (1986a,b) investigated the effect of 1,3-butadiene on haematological parameters in mice. Male B6C3F1 mice were exposed to 1,3-butadiene at 1250 ppm (2765 mg/m3), 6 hr/day, 6 days/week for 3 to 24 weeks. Treatment resulted in macrocytic-megaloblastic anaemia, including a decrease in circulating erythrocytes, total haemoglobin, and haematocrit and an increase in mean corpuscular volume. Analysis of bone marrow cells showed they had increased numbers of cells in S phase. These findings indicated the bone marrow to be an important target organ for 1,3-butadiene toxicity (Irons et al,1986a). In a further study, the potential effect of murine leukemia retroviruses on 1,3-butadiene-induced anaemia was investigated (Irons et al, 1986b). Male NIH Swiss mice were exposed to 1,3-butadiene at 1250 ppm (2765 mg/m3), 6 hr/day, 6 days/week for 6 weeks. NIH Swiss mice do not possess intact endogenous ecotropic type C murine leukemia retroviruses which may have played a role in 1,3-butadiene- induced anaemia in other mouse strains. Treatment resulted in macrocytic-megaloblastic anaemia and an 8-fold increase in circulating micronuclei. These findings confirmed that the bone marrow is an important target for 1,3-butadiene toxicity in mice that is independent of murine leukemia retrovirus background and expression.  

The effect of 1,3-butadiene on immune function in mice was investigated by Thurmond et al (1986) (see Section on Immunotoxicity).Exposure of mice to 1250 ppm (2766 mg/m3) 1,3-butadiene by inhalation 6 hr/ day, 5 days/ week, for 6 or 12 weeks caused some minor changes in immune function but there were no detectable toxicologically significant persistent immunological effects.

Human Information  

There is limited useful information on the (non-neoplastic) health effects of repeated exposure to 1,3-butadiene in humans, data prior to 2002 are summarised in the EU RAR (2002). One limited study (Cowles et al, 1994) showed no significant differences in health status or haematology parameters in workers exposed to 1,3-butadiene at a mean 8 h time weighted average of about 3.5 ppm (7.74 mg/m3) compared with a non-exposed group, even in a sub-group where the highest 1,3-butadiene exposure (8 h time weighted average) was about 10 ppm (22.1 mg/m3). A more recent study (Tsai et al, 2003) also showed no evidence of adverse haematological findings associated with exposure to 1,3-butadiene when workers from 2 plants were compared with a non-1,3-butadiene exposed group. Haematological parameters were compared in workers at two 1,3-butadiene plants who had participated in the Shell Butadiene Medical Surveillance Program from 1979 -2003 with a group of employees who had not participated in the program and therefore were not exposed to 1,3-butadiene (although they may been exposed to other chemicals). Exposure data showed that the 1,3-butadiene surveillance group for 1979-1996 had a mean overall exposure of 4.55 ppm (10.07 mg/m3) (8h, 10h and 12h-time weighted average); from 1997, this figure was 0.25 ppm (0.55 mg/m3). Before 1996 the OSHA exposure limit was 1000 ppm and post-1996 it was 1 ppm. Both facilities gave similar exposure results. There were no significant differences in 6 Complete Blood Count parameters (white blood cell count, lymphocyte count, red blood cell count, hemoglobin concentration, mean corpuscular volume, and platelet count) between the 1,3-butadiene surveillance group compared with the comparison group when compared on an individual plant basis or all results combined.

Long-term exposure of humans to 1,3-butadiene may result in an increased risk of lymphohaematopoietic cancer (see Section on Carcinogenicity). Studies of the causes of mortality of workers exposed to 1,3-butadiene have shown no increases in mortality due to lung cancer, cardiovascular disease and digestive system cancer indicating that 1,3-butadiene has no chronic effects on these organ systems in humans (Divine and Hartman 2001, Delzell et al 2006). These studies are described in the Section on Carcinogenicity. 

Long-term exposure of humans to 1,3-butadiene may result in lymphohaematopoietic cancer (see Section on Carcinogenicity). Studies of the causes of mortality of workers exposed to 1,3-butadiene have shown no increases in mortality due to lung cancer, cardiovascular disease and digestive system cancer indicating that 1,3-butadiene has no chronic effects on these organ systems in humans (Divine and Hartman 2001, Delzell et al 2006). These studies are described in the Section on Carcinogenicity.   

Conclusions  

1,3-Butadiene has low toxicity in the rat, with minimal effects seen after exposure to 8000 ppm (17701 mg/m3) for 2 years. Limited data suggests that 1,3-butadiene also has low toxicity in guinea pigs, rabbits and dogs. No chronic non-neoplastic effects were seen in humans either, although data is also limited. 1,3-Butadiene exhibits marked species differences in repeat dose toxicity via inhalation exposure. The mouse is the most sensitive species where the target organs are bone marrow, ovary and testis. The effects on the bone marrow are consistent with the development of tumours of the haematopoietic system in carcinogenicity tests (NTP 1984, 1993), whilst there is no clear evidence of effects on immune function.  

Although ovarian atrophy has been observed in mice exposed to 1,3-butadiene at concentrations as low as 6.25 ppm (13 mg/m3) severe generalised toxicity occurred in this study. The conclusion of the EU RAR (2002) was that “nouseful information on the dose-response relationship for non-neoplastic effects can be derived from the available long-term studies in this species, as tumour formation and tumour-related mortality dominated the response at all exposure levels in these studies (6.25 ppm and above). The only useful information in relation to repeated dose toxicity in the mouse comes from short-term repeated exposure studies.” Ovarian toxicity in mice was also reported in the 13 week study of Bevan et al (1996). It is noteworthy that the EU RAR (2002) omitted this study and therefore it was not included in its review and discussion on the dose-response relationship for ovarian toxicity but it is clear from this study that ovarian toxicity occurred at 1000 ppm in the absence of systemic toxicity. Mice are particularly sensitive to 1,3-butadiene-induced toxicity and there is evidence to indicate that ovarian atrophy is caused by the diepoxide metabolite of 1,3-butadiene (Doerr et al, 1995, 1996) which is produced in mice. Quantitative differences in the metabolism of 1,3-butadiene in rats and mice in the production and elimination of the epoxide metabolites (Swenberg et al, 2007) are believed to be partly responsible for the marked species difference in toxicity (see Section on, Toxicokinetics, Metabolism and Distribution), but there is also some interspecies difference in the response to the diepoxide itself (Doerr et al, 1996; Kao et al, 1999). Mode-of-action data for the diepoxide of 4-vinylcyclohexene (the dimer of 1,3-butadiene) indicates that follicular atrophy is mediated by a stimulation of apoptosis (Takai et al, 2003; Thompson et al, 2002). It is notable that ovarian atrophy is not observed in rats following exposure to 1,3-butadiene. The available data indicate that humans are similar to rats in that they do not readily produce the diepoxide. 

The NOAEC for repeat dose toxicity is therefore 1000 ppm (2212 mg/m3) as defined by the study of Owen et al (1987) in the rat.    

Additional References  

Doerr, JK, EA Hollis, and IG Sipes. (1996). Species difference in the ovarian toxicity of 1,3-butadiene epoxides in B6C3F1 mice and Sprague-Dawley rats. Toxicology 113:128-36.  

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)

Swenberg JA, Boysen G, Georgieva N, Bird MG, Lewis RJ. (2007). Future directions in butadiene risk assessment and the role of cross-species internal dosimetry. Chem Biol Interact. 166: 78-83.  

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.

Justification for classification or non-classification

1,3 -Butadiene is a flammable gas at room temperature and therefore dermal and oral exposure are unlikely. It has low sub-chronic inhalation toxicity and therefore does not warrant classification under Dir 67/548/EEC or GHS/CLP.