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Abstract for TR-546

Toxicology and Carcinogenesis Studies of Sodium Dichromate Dihydrate in F344/N Rats and B6C3F1 Mice (Drinking Water Studies)

CASRN: 7789-12-0
Chemical Formula: Na2Cr2O7
Molecular Weight: 298.0
Synonyms/Common Names: Chromic acid; dichromic acid, dihydrate; disodium dichromate dihydrate; chromium VI
Report Date: July 2008

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Abstract

Sodium dichromate dihydrate is one of a number of inorganic compounds containing hexavalent chromium (Cr VI) found in drinking water source supplies as a contaminant resulting from various industrial processes including electroplating operations, leather tanning, and textile manufacturing. Because of the lack of adequate experimental data on the toxicity and carcinogenicity of hexavalent chromium ingested orally and because hexavalent chromium has been found in drinking water source supplies, the California Congressional Delegation, the California Environmental Protection Agency, and the California Department of Health Services nominated hexavalent chromium to the National Toxicology Program for study. Results of 3-month toxicity studies in F344/N rats and B6C3F1, BALB/c, and am3-C57BL/6 mice were reported earlier in NTP Toxicity Report 72. In the current study, male and female F344/N rats and B6C3F1 mice were exposed to sodium dichromate dihydrate (greater than 99.7% pure) in drinking water for 2 years.

2-Year Study in Rats 

Groups of 50 male and 50 female rats were exposed to drinking water containing 0, 14.3, 57.3, 172, or 516 mg/L sodium dichromate dihydrate (equivalent to 0, 5, 20, 60, or 180 mg/L chromium) for 2 years (equivalent to average daily doses of approximately 0.6, 2.2, 6, or 17 mg sodium dichromate dihydrate/kg body weight for males and 0.7, 2.7, 7, or 20 mg/kg for females). Survival of exposed groups was similar to that of the control groups. Mean body weights of 516 mg/L males and females were less than those of the controls throughout the study. The lower body weights were partly attributed to poor palatability of the dosed water and consequent reductions in water consumption. Water consumption by 172 and 516 mg/L rats was less than that by the controls throughout the study. Exposure to sodium dichromate dihydrate caused a microcytic hypochromic anemia in rats that ameliorated with time.

Exposure to sodium dichromate dihydrate resulted in the development of neoplasms of the squamous epithelium that lines the oral mucosa and tongue. The incidences of squamous cell carcinoma in the oral mucosa of 516 mg/L male and female rats were significantly greater than those in the controls. The incidence in 172 mg/L females exceeded the historical control ranges for drinking water studies and for all routes of administration. The incidences of squamous cell papilloma or squamous cell carcinoma (combined) of the oral mucosa or tongue of 516 mg/L male and female rats were significantly greater than those in the controls.

Exposure concentration-related nonneoplastic liver lesions were observed in males and females exposed to 57.3 mg/L or greater. These included histiocytic cellular infiltration, chronic inflammation, fatty change (females), basophilic focus (males), and clear cell focus (females). Increased incidences of histiocytic cellular infiltration also occurred in the small intestine (duodenum), mesenteric lymph node, and pancreatic lymph node of males and/or females exposed to 57.3 mg/L or greater.

2-Year Study in Mice 

Groups of 50 male mice were exposed to drinking water containing 0, 14.3, 28.6, 85.7, or 257.4 mg/L sodium dichromate dihydrate (equivalent to 0, 5, 10, 30, or 90 mg/L chromium) for 2 years (equivalent to average daily doses of approximately 1.1, 2.6, 7, or 17 mg sodium dichromate dihydrate/kg body weight). Groups of 50 female mice were exposed to drinking water containing 0, 14.3, 57.3, 172, or 516 mg/L sodium dichromate dihydrate (equivalent to 0, 5, 20, 60, or 180 mg/L chromium) for 2 years (equivalent to average daily doses of approximately 1.1, 3.9, 9, or 25 mg/kg). Survival of exposed groups was similar to that of the control groups. Mean body weights of 257.4 mg/L males were less than those of controls from months 2 through 6 of the study, but by the end of the study, the mean body weight of 257.4 mg/L males was only slightly less than that of the control group. Mean body weights of 172 mg/L females were less than those of the controls for months 3 through 12 of the study, and mean body weights of 516 mg/L females were less than those of the controls from month 2 until the end of the study. By the end of the study, the mean body weight of 172 mg/L females was 8% less than that of the controls, and the mean body weight of 516 mg/L females was 15% less than that of the controls. The lower body weights were partly attributed to poor palatability of the dosed water and consequent reductions in water consumption. Water consumption by 85.7 and 257.4 mg/L males and 172 and 516 mg/L females was less than that by the controls throughout the study. A treatment-related microcytosis occurred in exposed mice; the mice were less affected than the rats.

The incidences of neoplasms of the small intestine (duodenum, jejunum, or ileum) were increased in exposed groups of male and female mice. The incidences of adenoma of the duodenum in 257.4 mg/L males and 172 and 516 mg/L females were significantly greater than those in the controls. The incidence of carcinoma of the duodenum was significantly increased in 516 mg/L females. The incidence of adenoma of the jejunum in 516 mg/L females was significantly increased compared to that in the controls. When the incidences of adenoma and carcinoma were combined for all sites of the small intestine, the incidences were significantly increased in 85.7 and 257.4 mg/L males and 172 and 516 mg/L females compared to those in the controls. The incidences in 57.3 mg/L females exceeded the historical control ranges for drinking water studies and for all routes of administration.

The incidences of diffuse epithelial hyperplasia were significantly increased in the duodenum of all exposed groups of male and female mice. The incidences of histiocytic cellular infiltration were significantly increased in the duodenum of 85.7 and 257.4 mg/L males and in 172 and 516 mg/L females. In the jejunum, the incidences of diffuse epithelial hyperplasia and histiocytic cellular infiltration were significantly increased in 516 mg/L females.

The incidences of histiocytic cellular infiltration of the liver in all exposed groups of females, of the mesenteric lymph node in all exposed groups of males and females, and of the pancreatic lymph node of 85.7 and 257.4 mg/L males and 172 and 516 mg/L females were significantly increased.

Tissue distribution studies showed that total chromium concentrations tended to increase with increasing exposure concentration and duration of exposure.

Conclusions 

Under the conditions of these 2-year drinking water studies, there was of carcinogenic activity clear evidence of sodium dichromate dihydrate in male and female F344/N rats based on increased incidences of squamous cell neoplasms of the oral cavity. There was clear evidence of carcinogenic activity of sodium dichromate dihydrate in male and female B6C3F1 mice based on increased incidences of neoplasms of the small intestine (duodenum, jejunum, or ileum).

Exposure to sodium dichromate dihydrate resulted in histiocytic cellular infiltration in the liver, small intestine, and pancreatic and mesenteric lymph nodes of rats and mice and diffuse epithelial hyperplasia in the small intestine of male and female mice.

Studies

Summary of the 2-Year Carcinogenesis Studies of Sodium Dichromate Dihydrate

 


 
Male
F344/N Rats
Female
F344/N Rats
Male
B6C3F1  Mice
Female
B6C3F1  Mice
Concentrations in drinking water 0, 14.3, 57.3, 172, or 516 mg/L
 
0, 14.3, 57.3, 172, or 516 mg/L
 
0, 14.3, 28.6, 85.7, or 257.4 mg/L
 
0, 14.3, 57.3, 172, or 516 mg/L
 
Body weights 516 mg/L group less than the control group
 
516 mg/L group less than the control group
 
Exposed groups similar to control group
 
172 and 516 mg/L groups less than control group
 
Survival rates 28/50, 30/50, 30/49, 36/50, 29/49
 
33/50, 32/50, 32/50, 36/50, 31/50
 
33/50, 35/50, 35/50, 38/50, 32/50
 
37/50, 39/50, 45/50, 42/50, 42/50
 
Nonneoplastic effects

Liver: infiltration cellular, histiocyte (1/50, 0/50, 2/49, 5/50, 34/49)

Small intestine, duodenum: infiltration cellular, histiocyte (0/48, 0/48, 6/47, 36/46, 47/48)

Lymph node, mesenteric: infiltration cellular, histiocyte (13/49, 11/50, 30/49, 39/50, 41/49)
 

Liver: infiltration cellular, histiocyte (1/50, 5/50, 21/50, 42/50, 47/50)

Small intestine, duodenum: infiltration cellular, histiocyte (0/46, 0/49, 1/48, 30/46, 47/50)

Lymph node, mesenteric: infiltration cellular, histiocyte (21/50, 18/50, 27/50, 36/50, 42/50)

Lymph node, pancreatic: infiltration cellular, histiocyte (17/29, 20/36, 23/30, 32/34, 27/33)
 

Small intestine, duodenum: epithelium, hyperplasia, diffuse (0/50, 11/50, 18/50, 42/50, 32/50); infiltration cellular, histiocyte (0/50, 2/50, 4/50, 37/50, 35/50)

Lymph node, mesenteric: infiltration cellular, histiocyte (14/47, 38/47, 31/49, 32/49, 42/46)

Lymph node, pancreatic: infiltration cellular, histiocyte (0/5, 2/13, 2/10, 5/8, 12/16)
 

Liver: infiltration cellular, histiocyte (2/49, 15/50, 23/50, 32/50, 45/50)

Small intestine, duodenum: epithelium, hyperplasia, diffuse (0/50, 16/50, 35/50, 31/50, 42/50); infiltration cellular, histiocyte (0/50, 0/50, 4/50, 33/50, 40/50)

Small intestine, jejunum: epithelium, hyperplasia, diffuse (0/50, 2/50, 1/50, 0/50, 8/50); infiltration cellular, histiocyte (0/50, 0/50, 0/50, 2/50, 8/50)

Lymph node, mesenteric: infiltration cellular,
histiocyte (3/46, 29/48, 26/46, 40/50, 42/50)

Lymph node, pancreatic: infiltration cellular, histiocyte (0/14, 1/12, 2/15, 7/14, 8/13)
 
Neoplastic effects

Oral mucosa: squamous
cell carcinoma (0/50,
0/50, 0/49, 0/50, 6/49)

Oral mucosa or tongue:
squamous cell papilloma
or squamous cell carcinoma (0/50, 1/50,
0/49, 0/50, 7/49)


 

Oral mucosa: squamous cell carcinoma (0/50, 0/50, 0/50, 2/50, 11/50)

Oral mucosa or tongue: squamous cell papilloma or squamous cell carcinoma (1/50, 1/50, 0/50, 2/50, 11/50)

Small intestine, duodenum: adenoma (1/50, 0/50, 1/50, 5/50, 15/50)

Small intestine, duodenum, jejunum, or ileum: adenoma (1/50, 1/50, 1/50, 5/50, 17/50); carcinoma (0/50, 2/50, 1/50, 3/50, 5/50); adenoma or carcinoma (1/50, 3/50, 2/50, 7/50, 20/50) 
 


 

Small intestine, duodenum: adenoma (0/50, 0/50, 2/50, 13/50, 12/50); carcinoma (0/50, 0/50, 0/50, 1/50, 6/50)

Small intestine, jejunum: adenoma (0/50, 1/50, 0/50, 2/50, 5/50)

Small intestine, duodenum, jejunum, or ileum: adenoma (0/50, 1/50, 2/50, 15/50, 16/50); carcinoma (1/50, 0/50, 2/50, 3/50, 7/50); adenoma or carcinoma (1/50, 1/50, 4/50, 17/50, 22/50)
 

Level of evidence of carcinogenic activity Clear evidence Clear evidence Clear evidence Clear evidence