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EC number: 200-262-8 | CAS number: 56-23-5
Repeated inhalation exposure of rats of both sexes to CTC vapor at 10 to 810 ppm for 13 wk induced mild to severe hepatoxicity including a preneoplastic lesion, as well as renal and hematological toxicities to a less severe extent. However, inhalation exposure of both sexes to CTC vapor did not produce any histopathological change in the respiratory tracts, including the nasal cavity, larynx, trachea and lungs. The present study confirmed the pathological findings of earlier inhalation studies, by demonstrating the increased liver weight, enhanced release of transaminases into plasma and fatty degeneration, fibrosis and cirrhosis. Inhalation exposure to high levels of CTC for 13 wk induced the hepatic altered cell foci mirrored by GST-P-positively stained hepatocytes as a preneoplastic lesion, while the low levels of CCl4 designated 10ppm for the most sensitive sign as fatty change, cytoplasmic globules and increased liver weight.
Table 1: Terminal body weight, and relative liver and kidney weights of rats exposed to CCl4 vapor by inhalation for 13 wk
No. of animals examined
Body weight (g)
Values indicate means. Significant difference; +: p 0.05 **: p0.01 by Dunnett's test.
Table 2. Hematological, blood biochemical and urinary parameters of the rats exposed to CCl4 vapor by inhalation for 13 wk
Red blood cell (106/μl)
Total bilirubin (mg/dl)
Values indicate means. Significant difference; *: p 0.05 **: p0.01 by Dunnett's test.AST: aspartate aminotransferase, : alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase. a: Number of animals whose urinary protein level exceeded 100 mg/dl was counted. b: blood collection failed for one rat
Table 3. Incidences and severities of selected histopathological lesions in the rats exposed to CCl4 vapor by inhalation for 13 wk
LiverFatty change: small droplet
Fatty change: large droplet
Altered cell foci
Acidophilic cell foci
Basophilic cell foci
Clear cell foci
Values indicate number of animals bearing lesion. The values in parentheses indicate the average of severity grade index of the lesion. The average of severity grade was calculated with the following equation. Σ (grade x number of animals with grade) / number of affected animals. Grade 1=slight, 2=moderate, 3=severe. Significant difference; *: p 0.05 **: p0.01 by chi-square test
The present study (Nagano 2007) presents for CTC a LOAEC of 64 mg/m³ (10 ppm) in rats for subchronic repeated dose toxicity via inhalation exposure (Treatment: 6 h/d, 5 d/week, 13 weeks). Basis are organ weight effects and fatty change in liver .
Subchronic toxicity of CTC was examined according to OECD guideline 413. F344 rats of both sexes were exposed by inhalation to 0, 10, 30, 90, 270 or 810 ppm (v/v) CTC vapor for 13 wk (6 h/d and 5 d/wk). Body weight development, food consumption and clinical signs were monitored during te course of the study. At the end of treatment, urinary parameters, haematology and clinical chemistry parameters were investigated. Furthermore, all animals underwent full macroscopic anc microscopic pathological evaluation.
In the high exposure levels at 270 and 810 ppm, altered cell foci in the livers, and fibrosis and cirrhosis in the rat liver were observed. Hematoxylin and eosin-stained altered cell foci of rats were recognized as glutathione-S-transferase placental form (GST-P) positive foci, which are preneoplastic lesions of hepatocarcinogenesis. The most sensitive endpoint of CTC-induce toxicity was fatty change with large droplets in rats of both sexes, as well as increased relative liver weight in male rats. Those endpoints were manifested at 10 ppm and the LOAEL was determined as 10 ppm for the hepatic endpoints in rats. Enhanced cytolytic release of liver transaminase into plasma in rats was observed at medium and high levels of inhalation exposure. Both CTC-induced hepatoxicity and nephrotoxicity were observed, but nephrotoxicity was manifested at higher exposure concentrations than hepatotoxicity.
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