Dibutyltin dichloride

Additional toxicological data

Administrative data

Endpoint:

additional toxicological information

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not reported

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Provided for information purposes only. Study evaluated the elimination of DBTC following i.v. exposure.

Data source

Reference

Reference Type:

publication

Title:

Repeated administration of a mild acute toxic dose of di-n-butyltin dichloride at intervals of 3 weeks induces severe lesions in pancreas and liver of rats

Author:

Merkord J. et al

Year:

2001

Bibliographic source:

Human & Experimental Toxicology, 20, 386-392

Materials and methods

Type of study / information:

Acute and repeated administration of a mild acute toxic dose of di-n-butyltin dichloride at intervals of 3 weeks induces severe lesions in pancreas
and liver of rats.

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Male inbred rats (LEW-1W, Karlsburg) weighing 150 ± 20 g body weight were used in this study. For i.v. administration, DBTC (Sigma-Aldrich Chemie, Steinheim) was dissolved first in 100% ethanol. Two parts of this solution were mixed with three parts glycerol. The animals (seven per group) treated with a single dose of DBTC (4 or 8 mg/kg body weight) were sacrificed 1, 4, and 7 days and 2, 3, 4, 6, 9, and 12 weeks after treatment. In the group treated with repeated doses of DBTC (4 mg/kg body weight) at intervals of 3 weeks, the animals were sacrificed 4 h after the last administration on days 21, 42, 63, and 84 after the first treatment. The control group received the solvent only at intervals of 3 weeks and the animals were sacrificed at the same time as the repeated DBTC group.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Dibutyltin dichloride

EC Number:

211-670-0

EC Name:

Dibutyltin dichloride

Cas Number:

683-18-1

Molecular formula:

C8H18Cl2Sn

IUPAC Name:

dibutyltin dichloride

Results and discussion

Any other information on results incl. tables

Control group:

No changes in pancreas, liver, or biliopancreatic duct morphology were noted in samples taken from control animals up to 12 weeks.

DBTC group (single dose of 8 mg/kg i.v.):

One day after DBTC treatment, an acute interstitial pancreatitis had developed with inflammatory cells, dilated acinar lumina, and scattered acinar cell necrosis. The biliopancreatic duct was dilated and a partial necrosis of the surface epithelium was observed. In the liver, edema of the portal tracts was the only sign of damage. One week after DBTC treatment, an acute interstitial pancreatitis with infiltrates of eosinophilic granulocytes, histiocytes, lymphocytes, macrophages, and plasma cells was observed. The biliopancreatic duct showed an extreme dilation and the total necrosis of the surface epithelium of the duct leads to adhesion and obstruction of the duct followed by cholestasis. In the liver, an acute inflammation of portal tracts and parenchymal necrosis in the perivenular zone were present. Two to four weeks after DBTC treatment, fibrotic areas and tubular complexes around the biliopancreatic duct were present. Intrahepatic bile duct hyperplasia and parenchymal necrosis were observed in the liver. Nine to 12 weeks after DBTC treatment, pancreatic fibrosis and early signs of liver cirrhosis were present.

DBTC group (single dose of 4 mg/kg i.v.):

One day after DBTC treatment, an interstitial edema was seen in the pancreas in the form of an enlarged space between the pancreatic acini, filled by some granulocytes and histiocytes. Four to seven days after administration of a single dose of 4 mg/kg DBTC i.v., a mild interstitial pancreatitis had developed. The changes in acinar cells were vacuolization, cystic degeneration, and single-cell necrosis. The biliopancreatic duct was minimally dilated and the biliopancreatic duct epithelium showed swollen epithelial cells and partial necrosis in some segments. In the liver, a mild inflammation of portal tracts was present. Four weeks after administration of DBTC, the pancreas and liver showed no changes and the biliopancreatic duct was normal.

DBTC group (repeated dose of 4 mg/kg i.v.):

In the first 3 weeks, we found the same result as in the DBTC group with single dose of 4 mg/kg DBTC i.v. Six weeks after repeated administration of 4 mg/kg DBTC i.v., the biliopancreatic duct was thicker than normal, and there was fibrosis in its wall and in the adjacent pancreas. In the liver, after repeated doses, the inflammation of the portal tracts was stronger and may be accompanied by some bile duct proliferation.

Twelve weeks after repeated administration of 4 mg/kg DBTC i.v., the biliopancreatic duct was extremely dilated and the pancreas showed an interstitial and periductal fibrosis. In the liver, signs of inflammation, isolate necrosis, and intrahepatic bile duct hyperplasia were present. When comparing these effects to the toxic effects after single administration of 8 mg/kg DBTC i.v., the lesions on repeated administration of 4 mg/kg DBTC were milder.

Pathobiochemistry:

Acute pancreatitis was indicated by significantly elevated levels of amylase and lipase. The activity of both enzymes was significantly increased from the basal level 1 day after treatment with DBTC and returned to normal values for amylase on day 4 and for lipase on day 7 after DBTC application. The significant increase in serum lipase activity within the first days after DBTC administration (4 or 8 mg/kg i.v.) is a pathobiochemical indicator of acute pancreatitis.

The significant increase of alkaline phosphatase activity and bilirubin concentration in serum 6-12 weeks after repeated treatment with DBTC (4 mg/kg i.v.) is a sign of cholestasis. Elevated serum levels of hyaluronic acid were found 9 and 12 weeks after repeated treatment with 4 mg/kg DBTC i.v. In comparison to single administration of 8 mg/kg body weight DBTC, the levels are lower on repeated treatment.

Results indicate that in 3 weeks, chosen as interval of repeated administration of 4 mg/kg DBTC in the present study, the organotin is eliminated from these organs.

Applicant's summary and conclusion

Conclusions:

Estimated half-life for elimination of dibutyltin dichloride administered to rats was 2 days.
Single administration of 4 mg/kg bw resulted in mild interstitial pancreatitis after 2-4 days following treatment; no effects after 21-28 days following treatment. Repeated i.v. administration of 4 mg/kg bw induced acute pancreatitis, biliopancreatic lesions, pancreatic fibrosis, and liver lesions.
Single administration of 8 mg/kg bw resulted in acute interstitial pancreatitis after 1 day following treatment. After 9-12 weeks following treatment, pancreatic fibrosis and signs of liver cirrhosis were evident.

Executive summary:

Di-n-butyltin dichloride (DBTC) induced thymus atrophy, bile duct lesions, pancreatitis, and liver lesions in rats. Depending on dose [ 6 and 8 mg/kg intravenous (i.v.) DBTC ] and time (1-24 weeks) , the lesions in pancreas developed to a pancreatic fibrosis and the lesions in liver to liver cirrhosis. A single i.v. administration of 4 mg/kg DBTC induces a mild interstitial pancreatitis after 2-4 days followed by a restitutio ad integrum after 21-28 days. In the present study, the lesions of biliopancreatic duct, pancreas, and liver of rats after repeated administration of 4 mg/kg DBTC i.v. at intervals of 3 weeks have been investigated. The histopathological changes of pancreas and liver were examined by light microscopy 1, 4, and 7 days and 2, 3, 4. 6, 9, and 12 weeks after administration of DBTC. Furthermore, pathobiochemical parameters of pancreatitis (amylase and lipase activity in serum) , liver lesions (alkaline phosphatase activity and bilirubin in serum), and of fibrosis (hyaluronic acid in serum) were studied. Repeated administration of rats with DBTC (4 mg/kg i.v.) at intervals of 3 weeks induced an acute interstitial pancreatitis and after 9-12 weeks, a pancreatic fibrosis and liver lesions (intrahepatic bile duct hyperplasia, inflammation in periportal tract, and necrosis). In serum, elevated levels of alkaline phosphatase. bilirubin, and hyaluronic acid were found. This study demonstrates that the organotin compound induces toxic effects on pancreas and liver of rats by repeated administration of lower doses at long intervals. The risk of exposure to organotin at long intervals should be considered.

Estimated half-life for elimination of dibutyltin dichloride administered to rats was 2 days. Single administration of 4 mg/kg bw resulted in mild interstitial pancreatitis after 2-4 days following treatment; no effects after 21-28 days following treatment. Repeated i.v. administration of 4 mg/kg bw induced acute pancreatitis, biliopancreatic lesions, pancreatic fibrosis, and liver lesions. Single administration of 8 mg/kg bw resulted in acute interstitial pancreatitis after 1 day following treatment. After 9-12 weeks following treatment, pancreatic fibrosis and signs of liver cirrhosis were evident.