Chloroform

Endpoint summary

Description of key information

For oral toxicity results from a reliable study in Sprague Dawley male rats (Chu et al. 1980) provided an oral LD50 value of 908 mg/kg body weight.
A study performed in Sprague Dawley rats (Bonnet et al. 1980) resulted in an acute inhalation LC50 value of 9.2 mg/L after 6 hours of exposure corresponding to 10.5 mg/L for 4 hours of exposure by applying Haber's law correction.
There were no reliable data for the dermal route.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Dose descriptor:

LD50

Value:

908 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Dose descriptor:

LC50

Value:

10 500 mg/m³

Additional information

Acute oral toxicity

The acute lethal toxicity varies depending on species, strain, sex and vehicle. In mice, the oral LD50 values range from 36 to 1366 mg chloroform per kg body weight (Pericin and Thomann 1979), whereas in rats the values range from 450 to 2000 mg chloroform per kg body weight (Kimura et al. 1971, Torkelson et al. 1976, Chu et al. 1980). For classification the results from the reliable study in Sprague Dawley rats are considered (Chu et al. 1980) which provided an oral LD50 value of 908 mg/kg body weight in male rats. This implies according to the CLP Regulation (EC) No 1272/2008 the classification with acute toxicity category 4 with the hazard statement harmful if swallowed.

Acute oral exposure to chloroform causes target-organ specific local and systemic effects at lower doses with the liver and kidneys as the target organs. The cytolethality and associated regenerative cell proliferation probably have a key role in the induction of renal tumours in rats. The oral NOAEL value for hepatotoxicty and nephrotoxicty and increase in labelling index (percent of nuclei in S-phase in liver cells) in male F-344 rats receiving chloroform dissolved in corn oil via oral gavage was 10 mg/kg body weight (Larson et al. 1995, Templin et al. 1996). However, an increase in cell proliferation in the kidney cortex was present in male Osborne-Mendel rats receiving 10 mg/kg body weight by oral gavage (Templin et al. 1996). A higher oral NOAEL of 30 mg/kg body weight/day has been reported for female F-344 rats based on serum enzyme changes indicative of liver damage (Keegan et al. 1998). Adverse effects occurring in the liver, kidneys and nasal passage are also observed after repeated oral exposure to chloroform and will be further discussed in the relevant section.

Acute inhalation toxicity

Depression of the central nervous system is the dominant symptom of acute inhalation toxicity of chloroform. The available rodent studies on the acute inhalation toxicity of chloroform are not reliable. However, in sum they give evidence that chloroform exhibits low acute inhalation toxicity. The study performed in male Sprague Dawley rats (Bonnet et al. 1980) resulted in an acute inhalation LC50 value of 9.2 mg/L after 6 hours of exposure. For classification, the relevant duration of exposure is 4 hours. Applying Haber’s law a corrected LC50 value for acute inhalation toxicity of 10.5 mg/L is calculated for chloroform. This value leads to the classification as acute category 4 with the hazard statement harmful if inhaled according to Regulation (EC) No 1272/2008.

Acute inhalation exposure to chloroform causes adverse systemic effects also at lower doses. Female B6C3F1 mice exposed to chloroform by inhalation of vapours for 4 days had a dose-dependent mild response of diffuse uniform lipid vacuolation in the liver, scattered individual hepatocyte necrosis and mild nasal lesions at exposure levels of 50 mg/m3 (Larson et al. 1995). F-344 rats exposed by inhalation to chloroform vapours for 4 days had minimal evidence of cellular alterations (vacuolation of PCT epithelium) in the kidney at levels of 1470 mg/m3 and nasal lesions within the lamina propria characterised by oedema, loss of deep Bowman's glands, periosteal hypercellularity and new bone growth in the proximal parts of the ethmoturbinates at levels of 50 mg/m3 (Templin et al. 1996). Adverse effects occurring in the liver, kidneys and nasal passage are also observed after repeated inhalation exposure to chloroform and will be discussed in the relevant section.

Acute dermal toxicity

Only one study on the dermal toxicity of chloroform is available, which is considered as not reliable.

Justification for classification or non-classification

According to EU directive 67/548/EEC, the substance is harmfull by inhalation (R20) and harmfull if swallowed (R22). However, during the revision of the classification of chloroform on September 2007, the TC C&L agreed to classify chloroform Category 3 "toxic if inhaled". In addition, the TC considered that the narcotic effects that would be covered by Xn/R20 would trigger classification STOT single 3 under the CLP regulation.

As chloroform exhibits rather low acute toxicity and based on acute toxicity data, the proposed GHS classification for chloroform is Category 4, "Harmful", with the hazard statements: harmful if swallowed and harmful if inhaled and STOT SE 3 with the hazard statement: may cause drowsiness and dizziness.