Registration Dossier

Administrative data

Description of key information

2,3-Dichloro-1,3-butadiene is moderately toxic after acute inhalation exposure with an LC50 of 2080 mg/m3/4 h in rats. There are no LD50 data available for the dermal route but studies in rats, mice, and rabbits provide evidence for systemic toxicity of 2,3-dichloro-1,3-butadiene after dermal application. The oral LD50 has been determined as 222 mg/kg for rats and 110 mg/kg for mice; target organs are the stomach, spleen, liver, and kidney.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Dose descriptor:
LD50
222 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Dose descriptor:
LC50
2 080 mg/m³

Additional information

Acutely lethal human exposure to CD has been associated with pulmonary edema, nervous system depression, narcosis and respiratory arrest. Nyström reported in 1948 that workers chronically exposed to CD might experience fatigue, chest pains, palpitation upon exertion, changes in disposition (i.e. irritability), dermatitis, and hair loss. These signs were most prominent among workers in the distillation and polymerization facilities. However, at the time, no analytical measurements were available on workplace CD concentrations. The effects of acute exposure to CD in mice, rats, cats and rabbits (strains not identified) were initially reported in 1936 by von Oettingen et al. Acute lethality was reported in both rats and cats after exposure for 8 h to CD at nominal exposure concentrations of around 1 mg/l (approximately 280 ppm)1 or greater. Clinical signs centered on the respiratory system irritation but also included restlessness and ‘progressive depression’. Irritation and respiratory depression were typically observed during exposure, while most deaths occurred after exposure and were due to pulmonary haemorrhage and edema. Mice appeared to be about twice as susceptible as rats, although the results for all species were highly variable and a clear dose response relationship was not always evident. In contrast, rabbits appeared to be less affected than the other species. In addition to the pulmonary injury, pathological changes in all species included vacuolar degeneration of renal tubular epithelium and diffuse hemorrhagic hepatic necrosis. At the time of von Oettingen’s studies in the 1930s, the stability of CD was not adequately characterized and the importance of preventing chemical reaction of CD with itself or air was not yet appreciated. The consequences of this were clearly evident in subsequent acute studies by Nyström, who showed that freshly distilled CD, administered subcutaneously to white rats (strain not specified), was about fourfold less lethal than that of polymerization-inhibited CD that had been allowed to oxidize (ostensibly forming more toxic oxidation products) by aging in air for several days prior to testing. Nyström also compared the pulmonary toxicity of subcutaneously administered fresh and aged CD. Once a threshold dose of 0.001 ml/kg was exceeded in rats, aged CD caused much more severe increases in lung weights than fresh CD. Histopathologic examination of the lungs showed hyperemia, edema and haemorrhage. Additionally, Nyström observed that aged CD caused the time for the onset of sedation to be reduced in mice (strain not reported) by as much as 50% compared with freshly distilled CD. These studies highlighted the need to understand the reactivity of CD and adequately characterize its purity when used in animal studies. More recent investigations using distilled CD (purity 100%) show that the acutely (4 h) lethal concentration of CD in male Crl:CD® (Sprague–Dawley derived) rats exceeds 2280 p.p.m. (deaths in one of six rats). Similar to von Oettingen’s study, clinical signs included respiratory irritation with death occurring 1–2 days post exposure; however, no signs of central nervous system depression were observed. To identify organs potentially affected by CD exposure, supplemental histopathologic evaluation of all major organs was performed on rats from the 3535 and 5308 p.p.m. groups for up to 14 days after exposure in an unpublished study. Histopathological changes were found only in the respiratory tract and liver. In the respiratory tract, desquamation and degeneration of bronchial and bronchiolar epithelium and pulmonary haemorrhage were found; however, the nose was not examined. Peribronchial/bronchiolar fibroblast proliferation and perivascular lymphocytic cuffing noted throughout the last week of recovery were considered to represent resolution of acute lung injury. In the liver, acute hepatocellular centrilobular or midzonal necrosis was observed with occasional sinusoidal inflammation and giant cell granuloma with fibrosis; the liver changes were observable only within 1 week after exposure.

2,3-Dichlorobuta-1,3-diene is moderately toxic after acute inhalation exposure with an LC50of 2080 mg/m3/4 h in rats. In another inhalation study on rats and mice with only 2 hours of exposure to 2,3-dichlorobuta-1,3-diene the LC50has been calculated as 4750 mg/m3for rats and 740 mg/m3for mice; the LC100is 8000 mg/m3for rats and 1000 mg/m3for mice and exposure to 3000 mg/m3and 400 mg/m3for 2 hours each, respectively, was tolerated by rats and mice. Thus 2,3-dichlorobuta-1,3-diene shows a very steep dose-effect-curve by acute inhalation probably due to its irritation potential in the respiratory tract leading to pulmonary edema, lung haemorrhages and necroses of the bronchiolar epithelium. There are no LD50data available for the dermal route but studies in rats, mice, and rabbits provide evidence for systemic toxicity of 2,3-dichlorobuta-1,3-diene after dermal application. The oral LD50has been determined as 222 mg/kg for rats and 110 mg/kg for mice; target organs are the stomach (necroses in the mucous membrane due to the irritant nature of the substance at the site of first contact) as well as spleen, liver, and kidney.

 

Justification for classification or non-classification

Classification according to GHS:

Acute oral toxicity – Acute Tox.3; H301: Toxic if swallowed

Acute inhalation toxicity – Acute Tox 2; H330: Fatal if inhaled

Acute dermal toxicity – no classification: data lacking

Aspiration hazard - Asp. Tox 1; May be fatal if swallowed and enters airway.

67/548/EEC Self-classification for acute toxicity - Xn; R 20/22 (harmful by inhalation and if swallowed),

Xn; R65 Harmful; Harmful: may cause lung damage if swallowed.