Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published NTP study report
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other:
Principles of method if other than guideline:
NTP protocol: 90-day sighting study for a subsequent carcinogenicity study
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Sodium dichromate dihydrate was obtained from Aldrich Chemical Company (Milwaukee, WI) in two lots (15301BI and 13822LI). The two lots were combined at the analytical chemistry laboratory, Battelle Memorial Institute (Columbus, OH), and assigned a new lot number (062001). Lot 062001 was used in the 3-month studies in F344/N rats and B6C3F1 mice (study 1). An additional shipment of lot 13822LI was obtained from Aldrich Chemical Company and used in the 3-month studies in male B6C3F1, BALB/c, and am3-C57BL/6 mice (study 2). Identity, purity, and stability analyses were conducted by the analytical chemistry laboratory (lots 062001 and 13822LI) and by the study laboratories at Southern Research Institute (Birmingham, AL; lot 062001) and Battelle Columbus Operations (Columbus, OH; lot 13822LI). Karl Fischer titration (lots 062001 and 13822LI) and elemental analysis using inductively coupled plasma-atomic emission spectroscopy (ICP-AES; lot 062001) were performed by Galbraith Laboratories, Inc. (Knoxville, TN); elemental analysis using ICP-AES (lot 13822LI) was performed by Battelle Northwest Operations (Richland, WA); and elemental analysis using proton-induced X-ray emission spectroscopy (PIXE; lots 062001 and 13822LI) was performed by Elemental Analysis Corporation (Lexington, KY). Reports on analyses performed in support of the sodium dichromate dihydrate studies are on file at the National Institute of Environmental Health Sciences.Lot 062001, an orange crystalline solid, was identified as sodium dichromate dihydrate by the analytical chemistry laboratory using X-ray diffraction (XRD), by the analytical chemistry laboratory and Galbraith Laboratories, Inc., using elemental analysis by ICP-AES, and by Elemental Analysis Corporation using elemental analysis by PIXE. Lot 13822LI, an orange crystalline solid, was identified as sodium dichromate dihydrate by the analytical chemistry laboratory using XRD, by the analytical chemistry laboratory and Battelle Northwest Operations using elemental analysis by ICP-AES, and by Elemental Analysis Corporation using elemental analysis by PIXE. The XRD powder patterns were consistent with a reference pattern. Elemental analyses for chromium and sodium were in agreement with the theoretical values for sodium dichromate dihydrate, and PIXE indicated the absence of significant metallic impurities.The moisture content of lots 062001 and 13822LI was determined by Karl Fischer titration and, for lot 13822LI, weight loss on drying was performed by the analytical chemistry laboratory. The purity of lot 062001 was determined by the analytical chemistry laboratory using differential scanning calorimetry (DSC), titration of the dichromate ion with sodium thiosulfate and potassium ferrocyanide, and speciation of the chromium ions using liquidchromatography-inductively coupled plasma-mass spectrometry (LC-ICP-MS) and by the study laboratory using potentiometric titrimetric analysis. The purity of lot 13822LI was determined by the analytical chemistry laboratory using DSC, titration of the dichromate ion with sodium thiosulfate and potassium ferrocyanide, and LC-ICP-MS and by the study laboratory using titration with sodium thiosulfate. For lot 062001, Karl Fischer titration indicated a moisture content of 11.62%, which is in agreement with the theoretical value of 12.09%. DSC indicated a purity of 99.73% ± 0.15%. Titration with sodium thiosulfate by the analytical chemistry laboratory indicated a purity of 99.7% ± 0.1%. Titration with sodium thiosulfate by the study
laboratory indicated purities of 101% and 102% relative to a frozen reference standard of the same lot. Titration with potassium ferrocyanide indicated a purity of 103.1% ± 0.2%. LC-ICP-MS indicated that the concentration of Cr III, if present, was less than 0.1%. The overall purity of lot 062001 was determined to be greater than 99.7%. For lot 13822LI, Karl Fischer titration indicated a moisture content of 9.16%, less than the theoretical value of 12.09%; however, the percentage weight loss on drying agreed well with the theoretical value. DSC indicated a purity of 99.10% ± 0.27%. Titration with sodium thiosulfate and potassium ferrocyanide at the analytical chemistry laboratory indicated purities of 99.1% ± 1.2% and 99.6% ± 1.6%, respectively. Titration with sodium thiosulfate at the study laboratory indicated a purity of 101.8%. LC-ICP-MS indicated that the concentration of Cr III, if present,
was less than 0.1%. The overall purity of lot 13822LI was determined to be greater than 99%. To ensure stability, the bulk chemical was stored at room temperature, protected from light in amber glass bottles (lot 062001) or in a white plastic bottle (lot 13822LI). During the studies, stability of the bulk chemical was monitored by the study laboratories using potentiometric titration (lot 062001) or titration of the dichromate ion with sodium thiosulfate (lot 13822LI). No degradation of the bulk chemical was detected.

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
3 months (90 days)
Frequency of treatment:
Continuous (exposure to drinking water)
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 62.5, 125, 250, 500, 1000 mg/l
Basis:
nominal in water
Remarks:
Doses / Concentrations:
0, 9, 15, 26, 45, 80 mg/kg bw/d
Basis:
actual ingested
Remarks:
Doses / Concentrations:
0, 3.1, 5.2, 9.1, 15.7, 27.9 mg/kg bw/d
Basis:
other: Cr (VI) equivalents
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment

Results and discussion

Effect levels

Dose descriptor:
NOAEL
Effect level:
62.5 mg/L drinking water
Sex:
male/female
Basis for effect level:
other: Incidences of epithelial hyperplasia of the duodenum were significantly increased in all exposed groups of mice.
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

All mice survived to the end of the study. Final mean body weights and body weight gains of mice exposed to 125 mg/L or greater and the body weight gains of 62.5 mg/L male mice were significantly less than those of the controls. Male and female mice exposed to 125 (except males at week 13), 250, 500, or 1000 mg/L consumed less water than the respective control groups. Exposure concentrations of 62.5, 125, 250, 500, and 1000 mg/L resulted in average daily doses of approximately 9, 15, 26, 45, and 80 mg/kg to mice. No clinical findings were attributed to sodium dichromate dihydrate exposure.

Haematology

Mice demonstrated an erythrocyte microcytosis (decrease in mean cell volume) similar to that seen in the NTP rat study. However, the mice were much less affected, and no contradictory data from hematocrit values or mean cell hemoglobin concentrations, as described for rats, occurred for mice. The decreases in mean cell hemoglobin reflected the mean cell volume decrease. Similar to the occurrence at week 14 in the rat studies, erythrocyte counts increased, and hemoglobin concentrations decreased, but only in females.

Organ weights

Absolute liver weights of males exposed to 250 mg/L or greater and females exposed to 500 or 1,000 mg/L were significantly less than those of the respective controls, but liver weights relative to body weights were unchanged. Relative kidney weights of males exposed to 1,000 mg/L were significantly greater than those of the control group. Other differences in organ weights were attributed to the reduced body weights of the mice.

Pathology

In the duodenum, the incidences of minimal to mild epithelial hyperplasia were significantly increased in all exposed groups, and severities increased slightly with increasing exposure concentration. Compared to the controls, the duodenal villi were short, thick, and blunted, the crypts elongated, and diffuse hyperplasia of the crypt epithelium extended towards the tips of the villi. The hyperplasic epithelial cells were tall, columnar, densely packed, and stained more basophilically than the shorter columnar epithelial cells lining the duodenal villi of the control mice. There were also increased numbers of mitotic figures in the hyperplastic epithelium. In addition, the epithelial cells lining the tips of the villi of many of the exposed mice were swollen and had vacuolated cytoplasm. Collectively, these duodenal lesions suggest regenerative hyperplasia secondary to previous epithelial cell damage or degeneration. In mice receiving 125 mg/L or greater, the incidences of minimal to mild histiocytic cell infiltration in the duodenum and mesenteric lymph nodes (except 500 mg/L males) were significantly increased. Histiocytic cell infiltration in the duodenum and the mesenteric lymph nodes was morphologically similar to that observed in the duodenum and pancreatic lymph nodes of rats. Slight glycogen depletion in hepatocytes was noted in exposed groups, but because it was associated with poor weight gain or diminished food intake, it is not considered to be a direct effect of treatment.

Reproductive tissue evaluations in found no significant differences from controls in left cauda epididymis, left epididymis, or left testis weights or in spermatid measurements or epididymal sperm motility for any of the exposed groups.

Applicant's summary and conclusion

Conclusions:
Administration of sodium dichromate in the drinking water to mice for 90 days caused effects on body weight and water consumption. Haematologocal investigations revealed a microcytic hypochromic anaemia consistent with an effect on iron homeostasis or haemoglobin synthesis. Histopathology revealed duodenal hyperplasia in all treated groups, consistent with a local irritant effect. A NOAEL could not be determined for this study due to histopathology ay the lowest dose level, however findings indicate a local rather than systemic effect.
Executive summary:

In study 1, groups of 10 male and 10 female B6C3F1 mice were given drinking water containing 0, 62.5, 125, 250, 500, or 1000 mg sodium dichromate dihydrate/L for 3 months. Dose levels were equivalent to average daily doses of approximately 9, 15, 26, 45, or 80 mg/kg; on a molecular weight basis, doses are equivalent to approximately 3.1, 5.2, 9.1, 15.7, and 27.9 mg/kg Cr (VI) per day. All mice survived to the end of the study. Reduced body weights occurred in male and female mice exposed to 125 mg/L or greater. Water consumption by male and female mice exposed to 125 mg/L or greater was generally less than that by the control groups. A microcytic hypochromic anemia was seen in mice, but the severity was less than in the comparable NTP rat study. The incidences of histiocytic cellular infiltration were generally significantly increased in the duodenum and the mesenteric lymph node of mice exposed to 125 mg/L or greater. Incidences of epithelial hyperplasia of the duodenum were significantly increased in all exposed groups of mice.