Chromium trioxide

Carcinogenicity

Description of key information

A number of carcinogenicity studies performed with chromium (VI) trioxide have been reported in the literature: two inhalation studies have been performed in female mice and two studies have been performed in the rat using intrabronchial implantation. A large amount of additional data is available on the carcinogenicity of Cr (VI) compounds using various exposure routes. The respiratory tract effects of chromium (VI) trioxide appear to be specific to this compound due to its corrosive nature, however once absorbed systemically the different chromium (VI) compounds are considered to be toxicologically equivalent.
Epidemiological data are also available and indicate that occupational exposure to chromium (VI) trioxide is linked to increased incidences of lung tumours.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Remarks:

NTP GLP guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Principles of method if other than guideline:

2-year drinking water study in rats focussing on carcinogenicity

GLP compliance:

yes

Specific details on test material used for the study:

Sodium dichromate dihydrate was obtained from Aldrich Chemical Company (Milwaukee, WI)

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms, Inc. (Germantown, NY)
- Age at study initiation: 6 to 7 weeks old
- Weight at study initiation: approx. 117 - 118g
- Housing: Core study rats were housed three (males) or five (females) per cage
- Diet: Irradiated NTP-2000 wafers (Zeigler Brothers, Inc., Gardners, PA), available ad libitum, changed weekly
- Water: Tap water (Birmingham municipal supply) via amber glass bottles (Wheaton Science Products, Millville, NJ) with Teflon®-lined plastic screw caps fitted with stainless steel, double-ball sipper tubes, available ad libitum, changed twice weekly
- Acclimation period: Core study animals were quarantined for 14 days before the beginning of the studies.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72° ± 3° F
- Humidity (%): 50% ± 15%
- Air changes (per hr): 10/hour
- Photoperiod (hrs dark / hrs light): 12 hours/day light and 12 hours/day dark

IN-LIFE DATES: From: October 2, 2002 (first exposure) To: September 29 to October 7, 2004 (necropsy dates)

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

The dose formulations were prepared approximately every 2 weeks by mixing sodium dichromate dihydrate with tap water. Formulations were stored in NALGENE® containers at room temperature for up to 42 days.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Stability studies of a 41.8 μg/mL dose formulation were performed by the analytical chemistry laboratory using ion chromatography. Stability was confirmed for at least 42 days for dose formulations stored in sealed NALGENE® containers, protected from light, at temperatures up to room temperature and for at least 7 days when stored in drinking water bottles under simulated animal room conditions.
Periodic analyses of the dose formulations of sodium dichromate dihydrate were conducted by the study laboratory using ultraviolet/visible/near infrared spectroscopy (350 to 390 nm). The dose formulations were analyzed approximately every 10 weeks. Of the dose formulations analyzed, all 44 for rats were within 10% of the target concentrations. Animal room samples and unused carboy storage samples of these dose formulations were also analyzed; all 16 animal room samples for rats were within 10% of the target concentrations. Fourteen of 16 carboy samples for rats were within 10% of the target concentrations.
The sodium dichromate dihydrate dosed water used in these studies was slightly acidic. Based on an equilibrium constant of 50, dichromate predominates at the highest exposure concentration and the chromate:dichromate ratio approaches 1 at the lowest exposure concentration. These ratios would be obtained when the starting material was a chromate or dichromate salt.

Duration of treatment / exposure:

2 years

Frequency of treatment:

Continuous

Post exposure period:

None

Dose / conc.:

14.3 mg/L drinking water

Remarks:

equivalent to 5 mg Cr(VI)/L drinking water (nominal); actually ingested: 0.6 mg/kg bw/d in males and 0.7 mg/kg bw/d in females

Dose / conc.:

57.3 mg/L drinking water

Remarks:

equivalent to 20 mg Cr(VI)/L drinking water (nominal); actually ingested: 2.2 mg/kg bw/d in males and 2.7 mg/kg bw/d in females

Dose / conc.:

172 mg/L drinking water

Remarks:

equivalent to 60 mg Cr(VI)/L drinking water (nominal); actually ingested: 6 mg/kg bw/d in males and 7 mg/kg bw/d in females

Dose / conc.:

516 mg/L drinking water

Remarks:

equivalent to 180 mg Cr(VI)/L drinking water (nominal); actually ingested: 17 mg/kg bw/d in males and 20 mg/kg bw/d in females

No. of animals per sex per dose:

50 per sex per dose

Control animals:

yes, concurrent no treatment

Details on study design:

Doses were seleted based on effects reported in previous studies and data from the 3-month toxicity studies (see NTP, 2007 in section on repeated dose toxicity)

Observations and examinations performed and frequency:

Observed twice daily; core study animals were weighed initially, weekly for the first 13 weeks, at 4-week intervals thereafter, and at the end of the studies; clinical findings for core study animals were recorded at 4-week intervals beginning at week 5. Water consumption by core study animals was recorded weekly for the first 13 weeks and every 4 weeks thereafter with each water consumption measurement covering a 7-day period.
Clinical Pathology
Blood was collected from the retroorbital sinus of clinical pathology male rats on days 4 and 22 and from special study male rats at 3, 6, and 12 months for hematology and clinical chemistry.
Hematology: hematocrit; hemoglobin concentration; erythrocyte, reticulocyte, and platelet counts; erythrocyte and platelet morphology; mean cell volume; mean cell hemoglobin; mean cell hemoglobin concentration; and leukocyte count and differentials
Clinical chemistry: urea nitrogen, creatinine, total protein, albumin, alanine aminotransferase, alkaline phosphatase, creatine kinase, sorbitol dehydrodrogenase, bile acids
Histopathology
Complete histopathology was performed on all core study animals. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone (with marrow), brain, clitoral gland, esophagus, eye, Harderian gland, heart, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, liver, lung, lymph nodes (mandibular and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular), testis (with epididymis and seminal vesicle), thymus, thyroid gland, tongue, trachea, urinary bladder, and uterus.

Sacrifice and pathology:

Method of Sacrifice: Carbon dioxide asphyxiation
Necropsies were performed on all core study animals

Clinical signs:

no effects observed

Description (incidence and severity):

No clinical findings were attributed to sodium dichromate dihydrate exposure.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Survival of exposed groups was similar to that of the control groups.
Survival rates for males were 28/50, 30/50, 30/49, 36/50, 29/49 and females 33/50, 32/50, 32/50, 36/50, 31/50 for treatment with 0, 14.3, 57.3, 172, or 516 mg/L, respectively.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of the 14.3, 57.3, and 172 mg/L groups of male and female rats were generally similar to those of the control groups throughout the study. Mean body weights of 516 mg/L males and females were less than those of controls throughout the study and by the end of the study were 88% and 89% that of the respective controls. The lower body weights were partly attributed to poor palatability of the dosed water and consequent reductions in water consumption rather than direct toxic effects of sodium dichromate dihydrate exposure.

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Description (incidence and severity):

Water consumption by 172 and 516 mg/L rats was less than that by the controls throughout the study. Decreases were evident from the first week of the study and continued until terminal sacrifice. During the second year of the study, the average water consumption was reduced by 15% and 22% and by 15% and 27% that of the controls in the 172 and 516 mg/L male and female rats, respectively. Drinking water concentrations of 14.3, 57.3, 172, or 516 mg/L resulted in average daily doses of approximately 0.6, 2.2, 6, or 17 mg sodium dichromate dihydrate/kg body weight for male rats and 0.7, 2.7, 7, or 20 mg/kg for female rats.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Exposure to sodium dichromate dihydrate caused a microcytic hypochromic anemia in rats that ameliorated with time.
An exposure con­centration-related erythrocyte microcytosis, evidenced by decreased mean cell volumes, occurred on day 4 and persisted throughout the study in the 172 and 516 mg/L groups; the 57.3 mg/L group demonstrated minor changes on day 22 and at months 3 and 6. In the 516 mg/L ani­mals, the severity of the microcytosis peaked with an approximately 20% to 25% decrease in red cell size on day 22 and at month 3. The severity of the microcytosis ameliorated with time. For example, by 12 months, the red cells of the 516 mg/L animals were only 5% smaller than those of the controls. Changes in the mean cell hemoglobin value mimicked the alterations in mean cell volume and were a reflection of the smaller red cells. Mean cell hemoglobin concentration demonstrated small, exposure concentration-related decreases (less than or equal to 10%) in the 172 and 516 mg/L animals. The mean cell hemoglobin concentration decreases were most severe on day 22 or at month 3; they ameliorated with time.
An exposure-related anemia, evidenced by decreases in hematocrit (instrument-derived), packed cell volume (spun microhematocrit), hemoglobin, and erythrocyte count values, developed by day 22 and affected the 57.3, 172, and 516 mg/L groups. The anemia was most severe on day 22 (an approximate 30% decrease in the 516 mg/L group) but resolved with time. In fact, at 3 months, erythrocyte counts were increased, in contrast to the lower hematocrit and hemoglobin values in the 516 mg/L group; the erythrocyte counts remained slightly elevated (less than 10%) in the higher-exposed animals out to the 12-month time point. The increased numbers of nucleated erythrocytes and/or reticulocytes in the 516 mg/L animals on day 22 and at month 3 were indicative of an erythropoietic response. Microscopic evaluation of the blood smears demonstrated increased poikilo­cytes, erythrocyte fragments/schizocytes, keratocytes, erythrocyte hypochromia, and microcytes that suggested increased erythrocyte injury or turnover. These changes were most prominent in the higher-exposed animals on day 22 and at month 3. Taken together, it appears that the erythropoietic tissues were able to respond to the anemia (also evidenced by slightly increased incidences of bone marrow hyperplasia in the core study male rats (0 mg/L, 4/50; 14.3 mg/L, 12/50; 57.3 mg/L, 7/49; 172 mg/L, 7/50; 516 mg/L, 6/49), but there was some ineffective erythropoiesis resulting in production of increased numbers of smaller erythrocytes. This effect was not observed at 6 or 12 months demonstrating that, with time, the animals adapted to exposure.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Increases in serum alanine aminotransferase activity occurred in the 57.3 mg/L or greater groups; however, serum sorbitol dehydrogenase activities and bile acid concentrations were unaffected. The severity of the serum alanine aminotransferase activity increases peaked at 3 months (e.g., greater than a twofold increase in the 516 mg/L group), stabilized, and remained elevated at this level to the 12-month time point. While there was an indication of a chronic inflammatory process of minimal severity in the liver, the lack of corroborating evidence in other markers of liver injury suggests that the alanine aminotransferase increases may have been related to enzyme induction in the liver instead of increased hepatocellular membrane leakage.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

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 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.

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

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. Squamous cell carcinomas were also observed in the oral mucosa of two 172 mg/L female rats and exceeded the historical control ranges for drinking water studies and for all routes of administration. One squamous cell carcinoma of the tongue occurred in a 14.3 mg/L male and one in a 172 mg/L female. A squamous cell papilloma of the oral mucosa occurred in one 516 mg/L male, and a squamous cell papilloma of the tongue occurred in one 516 mg/L male. One control and one 14.3 mg/L female had squamous cell papillomas of the tongue. 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.

Relevance of carcinogenic effects / potential:

Clear evidence of site-of-contact carcinogenicity was seen under the condtions of this study with sodium dichromate administered in drinking water. There was no evidence of systemic carcinogenicity.

Dose descriptor:

LOAEL

Effect level:

57.3 mg/L drinking water

Based on:

test mat.

Remarks:

equivalent to 0.77 mg Cr(VI)/kg bw/d (2.2 mg/kg bw/d in males)

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Dose descriptor:

LOAEL

Effect level:

516 mg/L drinking water

Based on:

test mat.

Sex:

male

Basis for effect level:

histopathology: neoplastic

Dose descriptor:

LOAEL

Effect level:

172 mg/L drinking water

Based on:

test mat.

Sex:

female

Basis for effect level:

histopathology: neoplastic

Critical effects observed:

not specified

Incidences of Neoplasms of the Oral Cavity in Rats in the 2-Year Drinking Water Study of Sodium Dichromate Dihydrate

	0 mg/L	14.3 mg/L	57.3 mg/L	172 mg/L	516 mg/L
Male
Number Necropsied	50	50	49	50	49
Oral Mucosa
Squamous Cell Papilloma a	0	0	0	0	1
Squamous Cell Carcinoma b
Overall Rate c	0/50 (0%)	0/50 (0%)	0/49 (0%)	0/50 (0%)	6/49 (12%)
Adjusted Rate d	0.0%	0.0%	0.0%	0.0%	13.6%
Terminal Rate e	0/28 (0%)	0/30 (0%)	0/30 (0%)	0/36 (0%)	1/29 (3%)
First Incidence (days)	—g	—	—	—	543
Poly-3 Test t	P<0.001	—h	—	—	P=0.015
Tongue
Squamous Cell Papilloma	0	0	0	0	1
Squamous Cell Carcinoma	0	1	0	0	0
Oral Mucosa or Tongue
Squamous Cell Papilloma or Squamous Cell Carcinoma i
Overall Rate	0/50 (0%)	1/50 (2%)	0/49 (0%)	0/50 (0%)	7/49 (14%)
Adjusted Rate	0.0%	2.4%	0.0%	0.0%	15.7%
Terminal Rate	0/28 (0%)	1/30 (3%)	0/30 (0%)	0/36 (0%)	1/29 (3%)
First Incidence (days)	^—	729 (T)	^—	^—	543
Poly-3 Test	P<0.001	P=0487	^—	^—	P=0.007
Female
Number Necropsied	50	50	50	50	50
Oral Mucosa
Squamous Cell Carcinoma j
Overall Rate	0/50 (0%)	0/50 (0%)	0/50 (0%)	2/50 (4%)	11/50 (22%)
Adjusted Rate	0.0%	0.0%	0.0%	4.6%	23.9%
Terminal Rate	0/33 (0%)	0/32 (0%)	0/32 (0%)	1/36 (3%)	2/31 (7%)
First Incidence (days)	^—	^—	^—	646	506
Poly-3 Test	P<0.001	^—	^—	P=0.233	P<0.001
Tongue
Squamous Cell Papilloma	1	1	0	0	0
Squamous Cell Carcinoma	0	0	0	1	0
Oral Mucosa or Tongue
Squamous Cell Papilloma or Squamous Cell Carcinoma k
Overall Rate	1/50 (2%)	1/50 (2%)	0/50 (0%)	2/50 (4%)	11/50 (22%)
Adjusted Rate	2.2%	2.3%	0.0%	4.6%	23.9%
Terminal Rate	0/33 (0%)	1/32 (3%)	0/32 (0%)	1/36 (3%)	2/31 (7%)
First Incidence (days)	618	729 (T)	^—	646	506
Poly-3 Test	P<0.001	P=0.756	P=0.503N	P=0.491	P=0.002

(T) Terminal sacrifice

a Number of animals with neoplasm

b Historical incidence for 2-year drinking water studies with controls given NTP-2000 diet (mean ± standard deviation): 0/350; all routes: 5/1,499 (0.3% ± 0.7%), range 0%-2%

c Number of animals with neoplasm per number of animals necropsied

d Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality

e Observed incidence at terminal kill

f Beneath the control incidence is the P value associated with the trend test. Beneath the exposed group incidence are the P values corresponding to pairwise comparisons between the controls and that exposed group. The Poly‑3 test accounts for differential mortality in animals that do not reach terminal sacrifice. A lower incidence in an exposed group is indicated by N.

g Not applicable; no neoplasms in animal group

h Value of statistic cannot be computed.

i Historical incidence for drinking water studies: 1/300 (0.3% ± 0.8%), range 0%-2%; all routes: 10/1,449 (0.6% ± 0.8%), range 0%-2%

j Historical incidence for drinking water studies: 0/300; all routes: 5/1,400 (0.4% ± 0.8%), range 0%-2%

k Historical incidence for drinking water studies: 3/250 (1.2% ± 1.1%), range 0%-2%; all routes: 14/1,350 (1.1% ± 1.6%), range 0%-6%

Incidences of Nonneoplastic Lesions of the Liver in Rats in the 2-Year Drinking Water Study of Sodium Dichromate Dihydrate

	0 mg/L	14.3 mg/L	57.3 mg/L	172 mg/L	516 mg/L
Male
Number Examined Microscopically	50	50	49	50	49
Infiltration Cellular, Histiocyte a	1 (1.0)b	0	2 (1.0)	5 (1.4)	34** (1.4)
Inflammation, Chronic	19 (1.1)	25 (1.2)	21 (1.3)	28* (1.1)	26 (1.3)
Basophilic Focus	22	28	29*	32*	30
Female
Number Examined Microscopically	50	50	50	50	50
Infiltration Cellular, Histiocyte	1 (1.0)	5 (1.0)	21** (1.3)	42** (2.0)	47** (2.6)
Inflammation, Chronic	12 (1.3)	21* (1.2)	28** (1.3)	35** (1.6)	39** (2.1)
Fatty Change	3 (3.3)	7 (3.6)	10* (2.5)	13** (2.5)	16** (2.8)
Clear Cell Focus	7	5	7	20**	7

* Significantly different (P≤0.05) from the control group by the Poly-3 test

** P≤0.01

a Number of animals with lesion

b Average severity grade of lesions in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked

Incidences of Selected Nonneoplastic Lesions in Rats in the 2-Year Drinking Water Study of Sodium Dichromate Dihydrate

	0 mg/L	14.3 mg/L	57.3 mg/L	172 mg/L	516 mg/L
Male
Small Intestine, Duodenum a	48	48	47	46	48
Infiltration Cellular, Histiocyte b	0	0	6* (1.2) c	36** (1.1)	47** (1.5)
Lymph Node, Mesenteric	49	50	49	50	49
Infiltration Cellular, Histiocyte	13 (2.0)	11 (1.5)	30** (1.9)	39** (2.1)	41** (2.1)
Hemorrhage	2 (1.5)	7 (1.1)	9* (1.3)	8* (1.1)	17** (1.3)
Lymph Node, Pancreatic	32	34	34	36	33
Infiltration Cellular, Histiocyte	17 (2.0)	22 (1.6)	17 (2.0)	17 (2.1)	25 (2.1)
Female
Small Intestine, Duodenum	46	49	48	46	50
Infiltration Cellular, Histiocyte	0	0	1 (1.0)	30** (1.0)	47** (1.2)
Lymph Node, Mesenteric	50	50	50	50	50
Infiltration Cellular, Histiocyte	21 (1.7)	18 (1.4)	27 (1.5)	36** (2.0)	42** (2.4)
Hemorrhage	11 (1.1)	13 (1.3)	16 (1.3)	14 (1.1)	21* (1.3)
Lymph Node, Pancreatic	29	36	30	34	33
Infiltration Cellular, Histiocyte	17 (2.0)	20 (1.9)	23 (2.6)	32** (2.8)	27 (3.0)
Salivary Gland	50	50	50	50	50
Atrophy	9 (1.3)	7 (1.4)	10 (1.2)	17* (1.4)	17 (2.1)

* Significantly different (P≤0.05) from the control group by the Poly-3 test

** P≤0.01

a Number of animals with tissue examined microscopically

b Number of animals with lesion

c Average severity grade of lesions in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked

Conclusions:

There was clear evidence of carcinogenic activity of sodium dichromate dihydrate in male and female F344/N rats based on increased incidences of squamous cell neoplasms of the oral cavity.

Executive summary:

Groups of 50 male and 50 female F344 rats were exposed to drinking water containing 0, 14.3, 57.3, 172, or 516 mg/L sodium dichromate dihydrate for 2 years. 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.

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Remarks:

NTP GLP guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Principles of method if other than guideline:

2-year drinking water study in mice focussing on carcinogenicity

GLP compliance:

yes

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms, Inc. (Germantown, NY)
- Age at study initiation: 6 to 7 weeks old
- Weight at study initiation: approx. 17.4 - 23.5 g
- Housing: core study mice were housed one (males) or five (females) per cage.
- Diet: Irradiated NTP-2000 wafers (Zeigler Brothers, Inc., Gardners, PA), available ad libitum, changed weekly
- Water: Tap water (Birmingham municipal supply) via amber glass bottles (Wheaton Science Products, Millville, NJ) with Teflon®-lined plastic screw caps fitted with stainless steel, double-ball sipper tubes, available ad libitum, changed twice weekly
- Acclimation period: Core study animals were quarantined for 14 days before the beginning of the studies.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72° ± 3° F
- Humidity (%): 50% ± 15%
- Air changes (per hr): 10/hour
- Photoperiod (hrs dark / hrs light): 12 hours/day light and 12 hours/day dark


IN-LIFE DATES: From: September 4, 2002 (first exposure) To: September 1 to 9, 2004 (necropsy dates)

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

The dose formulations were prepared approximately every 2 weeks by mixing sodium dichromate dihydrate with tap water. Formulations were stored in NALGENE® containers at room temperature for up to 42 days.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Stability studies of a 41.8 μg/mL dose formulation were performed by the analytical chemistry laboratory using ion chromatography. Stability was confirmed for at least 42 days for dose formulations stored in sealed NALGENE® containers, protected from light, at temperatures up to room temperature and for at least 7 days when stored in drinking water bottles under simulated animal room conditions.
Periodic analyses of the dose formulations of sodium dichromate dihydrate were conducted by the study laboratory using ultraviolet/visible/near infrared spectroscopy (350 to 390 nm). The dose formulations were analyzed approximately every 10 weeks. Of the dose formulations analyzed, all 84 for mice were within 10% of the target concentrations. Animal room samples and unused carboy storage samples of these dose formulations were also analyzed; 34 of 35 animal room samples for mice were within 10% of the target concentrations. 33 of 35 carboy samples for mice were within 10% of the target concentrations.
The sodium dichromate dihydrate dosed water used in these studies was slightly acidic. Based on an equilibrium constant of 50, dichromate predominates at the highest exposure concentration and the chromate:dichromate ratio approaches 1 at the lowest exposure concentration. These ratios would be obtained when the starting material was a chromate or dichromate salt.

Duration of treatment / exposure:

2 years

Frequency of treatment:

Continuous

Post exposure period:

none

Dose / conc.:

14.3 mg/L drinking water

Remarks:

males and females: equivalent to 5 mg Cr(VI)/L drinking water (nominal); actually ingested: 1.1 mg/kg bw/d

Dose / conc.:

57.3 mg/L drinking water

Remarks:

females only: equivalent to 20 mg Cr(VI)/L drinking water (nominal); actually ingested: 3.9 mg/kg bw/d

Dose / conc.:

172 mg/L drinking water

Remarks:

females only: equivalent to 60 mg Cr(VI)/L drinking water (nominal); actually ingested: 9 mg/kg bw/d

Dose / conc.:

516 mg/L drinking water

Remarks:

females only: equivalent to 180 mg Cr(VI)/L drinking water (nominal); actually ingested: 25 mg/kg bw/d

Dose / conc.:

28.6 mg/L drinking water

Remarks:

males only: equivalent to 10 mg Cr(VI)/L drinking water (nominal); actually ingested: 2.6 mg/kg bw/d

Dose / conc.:

85.7 mg/L drinking water

Remarks:

males only: equivalent to 30 mg Cr(VI)/L drinking water (nominal); actually ingested: 7 mg/kg bw/d

Dose / conc.:

257.4 mg/L drinking water

Remarks:

males only: equivalent to 90 mg Cr(VI)/L drinking water (nominal); actually ingested: 17 mg/kg bw/d

No. of animals per sex per dose:

50 per sex per dose

Control animals:

yes, concurrent no treatment

Details on study design:

Doses were seleted based on effects reported in previous studies and data from the 3-month toxicity studies (see NTP, 2007 in section on repeated dose toxicity)

Observations and examinations performed and frequency:

Observed twice daily; core study animals were weighed initially, weekly for the first 13 weeks, at 4-week intervals thereafter, and at the end of the studies; clinical findings for core study animals were recorded at 4-week intervals beginning at week 5. Water consumption by core study animals was recorded weekly for the first 13 weeks and every 4 weeks thereafter with each water consumption measurement covering a 7-day period.
Clinical Pathology
Blood was collected from the retroorbital sinus of clinical pathology female mice on days 22 and from special study female mice at 3, 6, and 12 months for hematology.
Hematology: hematocrit; hemoglobin concentration; erythrocyte, reticulocyte, and platelet counts; erythrocyte and platelet morphology; mean cell volume; mean cell hemoglobin; mean cell hemoglobin concentration; and leukocyte count and differentials
Histopathology
Complete histopathology was performed on all core study animals. In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone (with marrow), brain, clitoral gland, esophagus, eye, gallbladder, Harderian gland, heart, large intestine (cecum, colon, rectum), small intestine (duodenum, jejunum, ileum), kidney, liver, lung, lymph nodes (mandibular and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular), testis (with epididymis and seminal vesicle), thymus, thyroid gland, tongue, trachea, urinary bladder, and uterus.

Sacrifice and pathology:

Method of Sacrifice: Carbon dioxide asphyxiation
Necropsies were performed on all core study animals

Clinical signs:

no effects observed

Description (incidence and severity):

No clinical findings were attributed to sodium dichromate dihydrate exposure.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Survival of exposed groups was similar to that of the control groups.
Survival rates for males were 33/50, 35/50, 35/50, 38/50, 32/50 for treatment with 0, 14.3, 28.6, 85.7, or 257.4 mg/L, respectively and for females 37/50, 39/50, 45/50, 42/50, 42/50 for treatment with 0, 14.3, 57.3, 172, or 516 mg/L, respectively.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of 257.4 mg/L males were less than controls for the first 4 months 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 and 516 mg/L females were less than those of the controls for the first 8 months 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 control group. The lower body weights were partly attributed to poor palatability of the dosed water and consequent reductions in water consumption.

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Description (incidence and severity):

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.

Description (incidence and severity):

Similar to the rat study, an exposure-related microcytosis, evidenced by decreased mean cell volume values, occurred in mice. The female mice were less affected than the male rats. A minimal (less than or equal to 8%) decrease in mean cell volume occurred at all time points; the 172 and 516 mg/L groups were consistently affected. Changes in mean cell hemoglobin values mimicked the alterations in mean cell volume and reflected the smaller erythrocytes. Erythrocyte counts demonstrated small (less than or equal to 14%) increases at all time points with the 516 mg/L group most consistently affected. However, no other estimators of the erythron demonstrated any effects.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

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.

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

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.

Description (incidence and severity):

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

Relevance of carcinogenic effects / potential:

The results of this study indicate a clear carcinogenic effect of sodium dichromate on the mucosa of the small intestine in the mouse. Findings are associated with a local irritant effect.

Dose descriptor:

LOAEL

Effect level:

85.7 mg/L drinking water

Based on:

test mat.

Sex:

male

Basis for effect level:

histopathology: neoplastic

Dose descriptor:

LOAEL

Effect level:

57.3 mg/L drinking water

Based on:

test mat.

Sex:

female

Basis for effect level:

histopathology: neoplastic

Critical effects observed:

not specified

Incidences of Neoplasms and Nonneoplastic Lesions in the Small Intestine of Mice in the 2-Year Drinking Water Study of Sodium Dichromate Dihydrate

	0 mg/L	14.3 mg/L	28.6 mg/L	85.7 mg/L	257.4 mg/L
Male
Number Necropsied	50	50	50	50	50
Duodenum
Epithelium, Hyperplasia, Focal a	0	0	0	1 (3.0)^b	2 (3.5)
Epithelium, Hyperplasia, Diffuse	0	11** (2.0)	18** (1.6)	42** (2.1)	32** (2.1)
Infiltration Cellular, Histiocyte	0	2 (1.0)	4 (1.0)	37** (1.2)	35** (1.7)
Adenoma, Multiple	0	0	0	0	6*
Adenoma (includes multiple) c
Overall Rate d	1/50 (2%)	0/50 (0%)	1/50 (2%)	5/50 (10%)	15/50 (30%)
Adjusted Rate^e	2.2%	0.0%	2.3%	10.8%	32.9%
Terminal Rate f	0/33 (0%)	0/35 (0%)	1/35 (3%)	5/38 (13%)	10/32 (31%)
First Incidence (days)	665	—h	729 (T)	729 (T)	451
Poly-3 Test g	P<0.001	P=0.505N	P=0.751	P=0.106	P<0.001
Carcinoma^i
Overall Rate	0/50 (0%)	0/50 (0%)	0/50 (0%)	2/50 (4%)	3/50 (6%)
Adjusted Rate	0.0%	0.0%	0.0%	4.3%	6.8%
Terminal Rate	0/33 (0%)	0/35 (0%)	0/35 (0%)	2/38 (5%)	3/32 (9%)
First Incidence (days)	—	—	—	729 (T)	729 (T)
Poly-3 Test	P=0.011	—j	—	P=0.234	P=0.113
Jejunum
Adenoma k
Overall Rate	0/50 (0%)	0/50 (0%)	0/50 (0%)	0/50 (0%)	3/50 (6%)
Adjusted Rate	0.0%	0.0%	0.0%	0.0%	6.8%
Terminal Rate	0/33 (0%)	0/35 (0%)	0/35 (0%)	0/38 (0%)	2/32 (6%)
First Incidence (days)	—	—	—	—	714
Poly-3 Test	P=0.002	—	—	—	P=0.114
Carcinoma, Multiple	0	1	0	0	0
Carcinoma (includes multiple) l	0	2	0	1	2
Duodenum, Jejunum, or Ileum
Adenoma m
Overall Rate	1/50 (2%)	1/50 (2%)	1/50 (2%)	5/50 (10%)	17/50 (34%)
Adjusted Rate	2.2%	2.3%	2.3%	10.8%	37.2%
Terminal Rate	0/33 (0%)	1/35 (3%)	1/35 (3%)	5/38 (13%)	11/32 (34%)
First Incidence (days)	665	729 (T)	729 (T)	729 (T)	451
Poly-3 Test	P<0.001	P=0.755	P=0.751	P=0.106	P<0.001
Carcinoma^n
Overall Rate	0/50 (0%)	2/50 (4%)	1/50 (2%)	3/50 (6%)	5/50 (10%)
Adjusted Rate	0.0%	4.5%	2.3%	6.5%	11.4%
Terminal Rate	0/33 (0%)	2/35 (6%)	1/35 (3%)	3/38 (8%)	5/32 (16%)
First Incidence (days)	—	729 (T)	729 (T)	729 (T)	729 (T)
Poly-3 Test	P=0.014	P=0.233	P=0.492	P=0.123	P=0.028
Adenoma or Carcinoma^o
Overall Rate	1/50 (2%)	3/50 (6%)	2/50 (4%)	7/50 (14%)	20/50 (40%)
Adjusted Rate	2.2%	6.8%	4.6%	15.1%	43.8%
Terminal Rate	0/33 (0%)	3/35 (9%)	2/35 (6%)	7/38 (18%)	14/32 (44%)
First Incidence (days)	665	729 (T)	729 (T)	729 (T)	451
Poly-3 Test	P<0.001	P=0.296	P=0.485	P=0.032	P<0.001

	0 mg/L	14.3 mg/L	57.3 mg/L	172 mg/L	516 mg/L
Female
Number Necropsied	50	50	50	50	50
Duodenum
Epithelium, Hyperplasia, Focal	0	0	1 (2.0)	2 (3.0)	0
Epithelium, Hyperplasia, Diffuse	0	16** (1.6)	35** (1.7)	31** (1.6)	42** (2.2)
Infiltration Cellular, Histiocyte	0	0	4 (1.3)	33** (1.2)	40** (2.0)
Adenoma, Multiple	0	0	0	1	6*
Adenoma (includes multiple) p
Overall Rate	0/50 (0%)	0/50 (0%)	2/50 (4%)	13/50 (26%)	12/50 (24%)
Adjusted Rate	0.0%	0.0%	4.2%	27.8%	25.2%
Terminal Rate	0/37 (0%)	0/39 (0%)	2/45 (4%)	13/42 (31%)	11/42 (26%)
First Incidence (days)	—	—	729 (T)	729 (T)	693
Poly-3 Test	P<0.001	—	P=0.251	P<0.001	P<0.001
Carcinoma q
Overall Rate	0/50 (0%)	0/50 (0%)	0/50 (0%)	1/50 (2%)	6/50 (12%)
Adjusted Rate	0.0%	0.0%	0.0%	2.1%	12.6%
Terminal Rate	0/37 (0%)	0/39 (0%)	0/45 (0%)	1/42 (2%)	5/42 (12%)
First Incidence (days)	—	—	—	729 (T)	625
Poly-3 Test	P<0.001	—	—	P=0.507	P=0.019
Jejunum
Epithelium, Hyperplasia, Diffuse	0	2 (2.0)	1 (2.0)	0	8** (1.9)
Infiltration Cellular, Histiocyte	0	0	0	2 (1.0)	8** (1.6)
Adenoma, Multiple	0	0	0	0	1
Adenoma (includes multiple) r
Overall Rate d	0/50 (0%)	1/50 (2%)	0/50 (0%)	2/50 (4%)	5/50 (10%)
Adjusted Rate	0.0%	2.2%	0.0%	4.3%	10.6%
Terminal Rate	0/37 (0%)	1/39 (3%)	0/45 (0%)	2/42 (5%)	5/42 (12%)
First Incidence (days)	—	729 (T)	—	729 (T)	729 (T)
Poly-3 Test	P=0.002	P=0.504	—	P=0.246	P=0.035
Carcinoma s	1	0	2	2	1
Duodenum, Jejunum, or Ileum
Adenoma t
Overall Rate	0/50 (0%)	1/50 (2%)	2/50 (4%)	15/50 (30%)	16/50 (32%)
Adjusted Rate	0.0%	2.2%	4.2%	32.0%	33.7%
Terminal Rate	0/37 (0%)	1/39 (3%)	2/45 (4%)	15/42 (36%)	15/42 (36%)
First Incidence (days)	—	729 (T)	729 (T)	729 (T)	693
Poly-3 Test	P<0.001	P=0.504	P=0.251	P<0.001	P<0.001
Carcinoma u
Overall Rate	1/50 (2%)	0/50 (0%)	2/50 (4%)	3/50 (6%)	7/50 (14%)
Adjusted Rate	2.2%	0.0%	4.2%	6.4%	14.7%
Terminal Rate	1/37 (3%)	0/39 (0%)	2/45 (4%)	3/42 (7%)	6/42 (14%)
First Incidence (days)	729 (T)	—	729 (T)	729 (T)	625
Poly-3 Test	P<0.001	P=0.496N	P=0.521	P=0.319	P=0.037
Adenoma or Carcinoma v
Overall Rate	1/50 (2%)	1/50 (2%)	4/50 (8%)	17/50 (34%)	22/50 (44%)
Adjusted Rate	2.2%	2.2%	8.3%	36.3%	45.9%
Terminal Rate	1/37 (3%)	1/39 (3%)	4/45 (9%)	17/42 (41%)	20/42 (48%)
First Incidence (days)	729 (T)	729 (T)	729 (T)	729 (T)	625
Poly-3 Test	P<0.001	P=0.756N	P=0.198	P<0.001	P<0.001

(T) Terminal sacrifice

* Significantly different (P≤0.05) from the control group by the Poly-3 test

** P≤0.01

a Number of animals with lesion

b Average severity grade of lesions in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked

c Historical incidence for 2-year drinking water studies with controls given NTP-2000 diet (mean ± standard deviation): 6/299 (2.0% ± 2.2%), range 0%-6%; all routes: 9/1,549 (0.6% ± 1.3%), range 0%-6%

d Number of animals with neoplasm per number of animals necropsied

e Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality

f Observed incidence at terminal kill

g Beneath the control incidence is the P value associated with the trend test. Beneath the exposed group incidence are the P values corresponding to pairwise comparisons between the controls and that exposed group. The Poly‑3 test accounts for differential mortality in animals that do not reach terminal sacrifice. A lower incidence in an exposed group is indicated by N

h Not applicable; no neoplasms in animal group

i Historical incidence for drinking water studies: 1/299 (0.3% ± 0.8%), range 0%-2%; all routes: 3/1,549 (0.2% ± 0.8%), range 0%-4%

j Value of statistic cannot be computed.

k Historical incidence for drinking water studies: 0/299; all routes: 1/1,549 (0.1% ± 0.4%), range 0%-2%

l Historical incidence for drinking water studies: 5/299 (1.7% ± 1.5%), range 0%-4%; all routes: 25/1,549 (1.6% ± 2.2%), range 0%-8%

m Historical incidence for drinking water studies: 6/299 (2.0% ± 2.2%), range 0%-6%; all routes: 10/1,549 (0.7% ± 1.3%), range 0%-6%

n Historical incidence for drinking water studies: 6/299 (2.0% ± 1.8%), range 0%-4%; all routes: 30/1,549 (2.0% ± 2.2%), range 0%-8%

o Historical incidence for drinking water studies: 11/299 (3.7% ± 3.7%), range 0%-10%; all routes: 39/1,549 (2.6% ± 2.7%), range 0%-10%

p Historical incidence for drinking water studies: 1/350 (0.3% ± 0.8%), range 0%-2%; all routes: 3/1,648 (0.2% ± 0.6%), range 0%-2%

q Historical incidence for drinking water studies: 0/350; all routes: 1/1,648 (0.1% ± 0.4%), range 0%-2%

r Historical incidence for drinking water studies: 0/350; all routes: 0/1,648

s Historical incidence for drinking water studies: 2/350 (0.6% ± 1.0%), range 0%-2%; all routes: 5/1,648 (0.3% ± 0.7%), range 0%-2%

t Historical incidence for drinking water studies: 1/350 (0.3% ± 0.8%), range 0%-2%; all routes: 3/1,648 (0.2% ± 0.6%), range 0%-2%

u Historical incidence for drinking water studies: 3/350 (0.9% ± 1.1%), range 0%-2%; all routes: 8/1,648 (0.5% ± 0.8%), range 0%-2%

v Historical incidence for drinking water studies: 4/350 (1.1% ± 1.6%), range 0%-4%; all routes: 11/1,648 (0.7% ± 1.1%), range 0%-4%

Conclusions:

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).

Executive summary:

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).

Under the conditions of this 2 -year drinking water study, the NTP have concluded that there is 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 diffuse epithelial hyperplasia in the small intestine of male and female mice.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

0.77 mg/kg bw/day

Study duration:

chronic

Species:

rat

System:

gastrointestinal tract

Organ:

other: oral cavity (rats) and tumours of the small intestine (mice)

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

System:

other: respiratory tract

Organ:

lungs

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Chromium (VI) trioxide, sodium chromate, sodium dichromate and potassium dichromate are classified under Annex I to directive 67/548/EEC. Chromium (VI) trioxide is listed in Annex VI to Regulation (EC) No 1272/2008 under Index No 024-001-00-0 with the following harmonised classification:

Carc. 1A, H350 ‘May cause cancer’

This classification is consistent with the data of animals and occupationally exposed humans available in the literature and reviewed in the EU RAR. No change to this classification is proposed.

Additional information

Most of the available studies of carcinogenicity performed using chromium (VI) compounds have not been performed to GLP or to recognised guidelines, however the results of two NTP studies (in the rat and mouse) performed using sodium dichromate in the drinking water are available. These studies showed increased incidences of tumours of the oral cavity (rats) and tumours of the small intestine (mice); findings indicate a site-of contact effect associated with chronic irritation. The NTP have concluded that these studies both provide 'clear evidence' of carcinogenicity. The results of two published studies in female mice (Adachi et al, 1987; Adachi, 1988) exposed by inhalation to mists of chromic acid (aqueous chromium trioxide) for up to 12 months showed marginally (but not statistically significantly) increased incidences of lung tumours. The findings in these studies were associated with chronic irritation and corrosion of the respiratory tract. Similar findings of marginally increased tumour incidences were reported in one of two rat studies performed using intrabronchial implantation of pellets containing chromium (VI) trioxide (Laskin et al, 1970; Levy et al, 1986). A slight increase in the incidence of respiratory tract (lung and pharynx) tumours was seen at the highest exposure concentration in rats exposed to aerosols of sodium dichromate (Glaser et al, 1986). A clear increase in the incidence of lung tumours was seen in a study using intratracheal instillation of sodium dichromate (Steinhoff et al, 1985).

The carcinogenicity of chromium (VI) trioxide and other chromium (VI) salts have been extensively reviewed by the UK Health and Safety Executive (HSE, 1989); the UK Institute of Occupational Health (IOH, 1997) and most recently in the EU RAR (2005).

The EUR RAR summarised and reviewed the results of a number of studies of various designs and reliability which were designed to investigate the potential of water-soluble Cr (VI) compounds to cause respiratory tract carcinogenicity. This review also incorporates the studies previously reviewed by the HSE and IOH. The results of these studies were consistent in either demonstrating or indicating carcinogenicity to the respiratory tract following inhalation, instillation or implantation. In the case of the oral route, any systemic carcinogenic potential is limited by poor absorption from the gastrointestinal tract, and reduction to Cr (III) within the gastrointestinal tract; although site of contact activity may remain an issue. Similar considerations also apply to the skin. No studies of carcinogenicity following dermal exposure are available, however studies are not required due to the relatively low systemic availability by this route and the reduction of Cr (VI) to Cr (III).

Overall, water-soluble Cr (VI) compounds covered are considered to have proven or suspect carcinogenic potential. Most importantly, occupational (inhalation) exposure to chromium (VI) trioxide has been linked to increased incidences of lung cancer, therefore this compound was considered by the EU RAR to be a human carcinogen.

Water-soluble hexavalent chromium compounds are genotoxic in vitro and in vivo. However, the reduction of Cr (VI) to Cr (III) in the body (e.g. saliva, gastric juice, erythrocyte) may explain the lack of carcinogenicity of Cr (VI) at sites distant from the site of exposure. Nevertheless, from the available information, and taking into account the genotoxic potential of these substances, it is not possible to identify any dose-response relationship or thresholds for this effect. This potential is assumed for all Cr (VI) compounds.