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Carcinogenicity

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Description of key information

Carcinogenicity: Weight of evidence: experimental results: oral studies with rats and mice by administration in drinking water (for 80 or 85 weeks) and dermal studies with female mice (for 51 weeks). Under these conditions, there was no evidence of carcinogenic activity for sodium chlorite in rats and mice.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The experimental design of the long-term carcinogenicity tests was essentially similar to that published in the guidelines of the National Cancer Institute. No data on GLP.
Principles of method if other than guideline:
The experimental design of the long-term carcinogenicity tests was essentially similar to that published in the guidelines of the National Cancer Institute.
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan Inc., Kanagawa.
- Age at study initiation: 4- to 6-week-old
- Diet (e.g. ad libitum): Animals were allowed free access to basal diet (CRF1, Charles River).
- Water (e.g. ad libitum): Ad libitum.
Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
Sodium chlorite was dissolved in distilled water and administered orally to animals as their drinking water ad libitum.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
85 weeks (This study was prematurely terminated at week 85 because of wide-spread Sendai viral infection in all groups, necessitating immediate sacrifice of all survivors).
Frequency of treatment:
Daily
Dose / conc.:
300 ppm (nominal)
Dose / conc.:
600 ppm (nominal)
No. of animals per sex per dose:
50 male and 50 female rats per dose.
Control animals:
yes, concurrent vehicle
Details on study design:
The two dose levels were determined on the basis of preliminary 13-week tests, as the maximum tolerated dose (MTD) and 1/2 MTD.
Positive control:
No data
Observations and examinations performed and frequency:
The animals were observed daily. Consumption of water and body weights were recorded.
Sacrifice and pathology:
Dead animals and those found moribund were autopsied immediately.At termination of the tests, all surviving animals were anesthetized by ether inhalation to collect blood for hematologic and serum biochemical analysis.At necropsy, organs were grossly examined, excised, and weighed. They were stained with hematoxylin and eosin after routine histological processing.
Statistics:
The data were statistically analyzed using either the chi-square test, Fisher's exact probability test, or Student's t-test.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
no effects observed
Details on results:
- At necropsy, pneumonias were found in all animals, and an abscess of the lung had developed in some cases.- Percentages of survivors at week 85 were 86%, 60%, and 68% in males and 100%, 88%, and 94% in females, respectively, in high-dose (600 ppm), low-dose (300 ppm), and control groups.- Body weight increase was inhibited in a dose-dependent manner in both males and females.- Drinking water intake in treated animals was slightly lower than that in control animals of both sexes.- Serum biochemistry analysis revealed that levels of glutamic oxaloacetic transaminase in the liver were significantly decreased in the high-dose males.- Hematalysis and urinalysis revealed no significant in blood or urine.- No statistically significant differences in the incidence of tumor-bearing animals were observed between treatment and control groups of either sex- No statistically significant differences in the rates of tumor development in any organs were observed between treated and control animals of either sex.
Relevance of carcinogenic effects / potential:
Sodium chlorite was shown to be noncarcinogenic in rats.
Key result
Dose descriptor:
NOEL
Effect level:
>= 32.1 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: carcinogenicity
Key result
Dose descriptor:
NOEL
Effect level:
>= 40.9 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: carcinogenicity
Key result
Critical effects observed:
no

Sodium chlorite was shown to be non-carcinogenic in rats.

Conclusions:
No statistically significant differences were observed in the incidences of tumor formation between treated and control groups of both sexes.
Executive summary:

Long-term in vivo carcinogenicity tests of sodium chlorite has been conducted in Japan. In this investigation, groups of approximately 50 male and 50 female F344 rats were given solutions of the compounds as their drinking water ad libitum at two dose levels determined on the basis of preliminary 13-week tests. Control animals were given distilled water. Sodium chlorite was given to rats of both sexes at a dose of 600 or 300 ppm for 85 weeks. Daily consumption of sodium chlorite (mg/kg body weight/day) was 32.1 and 18.0 in males and 40.9 and 28.3 in females, respectively, for high- and low-dose groups.

No statistically significant differences were observed in the incidences of tumor formation between treated and control groups of both sexes.

Sodium chlorite was shown to be noncarcinogenic in rats.

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The experimental design of the long-term carcinogenicity tests was essentially similar to that published in the guidelines of the National Cancer Institute. No data on GLP.
Principles of method if other than guideline:
The experimental design of the long-term carcinogenicity tests was essentially similar to that published in the guidelines of the National Cancer Institute.
GLP compliance:
not specified
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Charles River Japan Inc., Kanagawa.
- Age at study initiation: 4- to 6-week-old
- Diet (e.g. ad libitum): Animals were allowed free access to basal diet (CRF1, Charles River).
- Water (e.g. ad libitum): Ad libitum.
Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
Sodium chlorite was dissolved in distilled water and administered orally to animals as their drinking water ad libitum.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
85 weeks
Frequency of treatment:
Daily
Dose / conc.:
250 ppm (nominal)
Dose / conc.:
500 ppm (nominal)
No. of animals per sex per dose:
50 male and 50 female mice per dose.
Control animals:
yes, concurrent vehicle
Details on study design:
The two dose levels were determined on the basis of preliminary 13-week tests, as the maximum tolerated dose (MTD) and 1/2 MTD.
Positive control:
No data
Observations and examinations performed and frequency:
The animals were observed daily. Consumption of water and body weights were recorded.
Sacrifice and pathology:
Dead animals and those found moribund were autopsied immediately.At termination of the tests, all surviving animals were anesthetized by ether inhalation to collect blood for hematologic and serum biochemical analysis.At necropsy, organs were grossly examined, excised, and weighed. They were stained with hematoxylin and eosin after routine histological processing.
Statistics:
The data were statistically analyzed using either the chi-square test, Fisher's exact probability test, or Student's t-test.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Description (incidence):
- Survival percentages at the end of the study were 86%, 94%, and 70% in males and 100%, 100%, and 94% in females, respectively, in high-dose, low-dose, and control groups.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
- Body weight increases were comparable among all groups of either sex.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
- The incidences of liver tumors were higher in treated males than in control males. These tumors were histologically diagnosed as hyperplastic nodules or hepatocellular carcinomas. The combined incidences of these tumors were significantly different in males of the low-dose group (p < 0.05). The incidences of hyperplastic nodules of the liver in males were significantly higher in both high- and low-dose groups (p < 0.05), although the incidences did not exhibit a dose-related effect. Also, the combined incidences of adenomas and adenocarcinomas and that of adenomas of the lung were significantly higher in males of the high-dose group (p < 0.05). Relatively high tumor rates were observed for malignant lymphomas and/or leukemias and adenomas of the Harderian gland in both sexes, and for tumors of the liver and the lung in females of all groups. Of these, the incidences of malignant lymphomas and/or leukemias in the high-dose female group were smaller by a statistically significant margin.
Relevance of carcinogenic effects / potential:
The results for mice were evaluated as inconclusive.
Key result
Dose descriptor:
NOEL
Effect level:
>= 500 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: carcinogenicity
Remarks on result:
other: The results for mice were evaluated as inconclusive.
Key result
Critical effects observed:
not specified
Conclusions:
In males, the combined incidences of hyperplastic nodules and hepatocellular carcinomas of the liver in a low-dose group, and adenomas and adenocarcinomas of the lung in a high-dose group, were marginally increased compared to controls (p < 0.05). However, these incidences in treated males were within the range of values of historical control data. The results were evaluated as inconclusive.
Executive summary:

Long-term in vivo carcinogenicity tests of sodium chlorite has been conducted in Japan. In this investigation, groups of approximately 50 male and 50 female B6C3F1 mice were given solutions of the compounds as their drinking water ad libitum at two dose levels determined on the basis of preliminary 13 -week tests. Control animals were given distilled water. Sodium chlorite was administered to mice at a concentration of 500 or 250 ppm for 85 weeks.

In males, the combined incidences of hyperplastic nodules and hepatocellular carcinomas of the liver in a low-dose group, and adenomas and adenocarcinomas of the lung in a high-dose group, were marginally increased compared to controls (p < 0.05). However, these incidences in treated males were within the range of values of historical control data.

The results for mice were evaluated as inconclusive.

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Test method was similar to OECD guideline 451, but only two dose levels were tested. No data on GLP.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
yes
Remarks:
(Only two dose levels were tested)
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Co., Japan Inc., Atsugi.
- Age at study initiation: 6 weeks old- Housing: They were housed in wire cages (2 males or 2 females/cage) in an air-conditioned room.
- Diet (e.g. ad libitum): They were given pellet diet (CRF-1; Charles River Co. Japan Inc., Atsugi). It was freely available.
- Water (e.g. ad libitum): Tap water, ad libitum.
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2 ºC
- Humidity (%): 55 ± 5 %
Route of administration:
oral: drinking water
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
85 weeksA longer experiment was planned, but because of infection with Sendai virus, all rats were killed in week 85.
Frequency of treatment:
Daily
Dose / conc.:
0.06 other: % in water
Dose / conc.:
0.03 other: % in water
No. of animals per sex per dose:
50 male and 50 female rats per group (also in the control group)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels used were chosen on the basis of the results of a preliminary subacute (12 weeks) experiment.
Observations and examinations performed and frequency:
The rats were weighed every one or two weeks and their water consumption was recorded every 5 weeks.Fresh urine samples were taken from 10 rats of each sex in each group in week 85 and urinary protein, glucose, ketones, urobilinogen and pH were measured with multistick III (Sankyo).BIood samples were taken from 10 rats of each sex from each group in week 85 for measurements of white blood cells, red blood cells, hemoglobin, the hematocrit, total protein, A/G, ALP, GOT, GPT, total cholesterol, BUN, Na, K, Cl and BS at the Ina Clinical Laboratory Inc., Iga Ueno.
Sacrifice and pathology:
A complete autopsy was performed on all animals, including those that died or became moribund during the experiment.AIl organs were carefully examined and samples were fixed in buffered neutral 10 % formalin, embedded in paraffin, and routinely stained with hematoxylin and eosin. Effective numbers of rats demonstrated the number of rats, killed in week 85.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Description (incidence):
In week 85, survival rates of rats of both sexes treated with 0.03 % sodium chlorite were the lowest. The numbers of surviving rats in week 85 were for males 43 in the 0.06 % group, 30 in the 0.05 % group and 34 in the control group, and for females, 50 in the 0.06 % group, 44 in the 0.03 % group and 47 in the control group.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The body weight of male and female rats treated with sodium chlorite tended to be less than of control rats, except for that of the male rats treated with 0.03 % sodium chlorite in 60 weeks. But no significant differences were found between the values in the three groups.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Sodium chIorite reduced the water consumption of both males and females. Sodium chlorite intakes were reported to be 18 and 32 mg/kg bw per day for males and 28 and 41 mg/kg bw per day for females.
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Description (incidence and severity):
Urine analyses, hematological findings and the results of laboratory tests of serum showed no significant differences between the treated and control rats except in the GOT level in males in the 0.06 % treated group. Anemia was not detected in week 85 in this study.
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The mean weights of the brain, heart, lung, liver, spleen, kidney and testis in week 85 showed no significant differences between the values in the three groups.
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
The incidences of tumor-bearing males were 83 % (36/43) in the 0.06 % sodium chlorite group, 76 % (23/30) in the 0.03 % sodium chlorite group and 82 % (28/34) in the control group, while the corresponding figures for females were 42 % (21/50), 31 % (14/44) and 31 % (15/47). Tumors developed in the testis, uterus, pituitary gland, tiryroid gland (in males) and adrenal gland (in males) of treated and control rats. Hyperplastic foci of the liver were observed in males in the 0.06 % sodium chlorite group at an incidence of 9 %, but no tumors of the liver were observed. The incidences of tumors in all organs were not significantly different in the three groups.Besides tumors, pneumonia due to Sendai virus infection was observed, but no remarkable histological changes of the kidney or testis were seen in test rats.
Histopathological findings: neoplastic:
no effects observed
Relevance of carcinogenic effects / potential:
No evidence was obtained that sodium chlorite had a carcinogenic effect in rats.
Key result
Dose descriptor:
NOEL
Effect level:
>= 32 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: carcinogenicity
Key result
Dose descriptor:
NOEL
Effect level:
>= 41 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: carcinogenicity

No evidence was obtained that sodium chlorite had a carcinogenic effect in rats.

Conclusions:
Tumors developed in the testis, uterus, pituitary gland, thyroid gland and adrenal gland of both treatment and control rats, but the incidences of tumors and nonneoplastic lesions in the three groups were not significantly different.Thus, no evidence was obtained that sodium chlorite had a carcinogenic effect in rats.
Executive summary:

The carcinogenic effect of the additton of sodium chlorite to the drinking water of male and female F-344 rats was examined with a method comparable to OECD guideline 451. Groups of 50 male and 50 female rats were given 0.06 % sodium chlorite (group I) or 0.03 % sodium chlorite (group II), or tap water to drink for 85 weeks. Hematological examinations, laboratory examinations of the serum and urine, and measurements of organ weights showed no significant differences between the groups in week 85. Tumors developed in the testis, uterus, pituitary gland, thyroid gland and adrenal gland of both treatment and control rats, but the incidences of tumors and nonneoplastic lesions in the three groups were not significantly different. Thus, no evidence was obtained that sodium chlorite had a carcinogenic effect in rats.

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Test method was similar to OECD guideline 451, but only two dose levels were tested. No data on GLP.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
yes
Remarks:
(Ony two dose levels were tested)
GLP compliance:
not specified
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Shizuoka Laboratory Center (Shizuoka, J apan).
- Age at study initiation: 6 weeks old
- Housing: Animals were housed five to six in plastic cages, with wood chips as bedding.
- Diet (e.g. ad libitum): Mice were given a pellet diet (CRF-1; Charles River Japan, Inc., Kanagawa, Japan) ad libitum.
- Water (e.g. ad libitum): Ad libitum.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2 ºC
- Humidity (%): 55 ± 10 %
- Photoperiod: 12 hrs dark / 12 hrs light
Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
The drinking water was prepared and supplied fresh three times a week in light-proof bottles.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
80 weeks
Frequency of treatment:
Daily
Post exposure period:
After 80 weeks, the animals were returned to distilled water without sodium chlorite. The withdrawal may further progress the induced tumor growth or regress reversible proliferative lesions, which makes a histological evaluation of test compounds easier.All mice were sacrificed 85 weeks from the beginning of the experiment.
Dose / conc.:
0.025 other: % in water
Dose / conc.:
0.05 other: % in water
No. of animals per sex per dose:
50 female and 50 male mice were used per dose.
Control animals:
yes, concurrent no treatment
Details on study design:
The high dose was chosen after a preliminary 13-week subacute toxicity study. In the subacute toxicity study, nine doses of sodium chlorite, 0, 0.00625, 0.0125, 0.025, 0.05, 0.1, 0.25, 0.5, and 1% in drinking water, were used. Mice given higher doses than 0.25 % died of dehydration due to a strong smell of the sodium chlorite-containing water.
Positive control:
No data
Observations and examinations performed and frequency:
The animals were observed daily for abnormalities.Individual body weights were recorded weekly for the first 13 weeks and every other week thereafter.Water consumption was measured over the 1-day period before each weighing.
Sacrifice and pathology:
After 85 weeks, surviving animals were deprived of food, but not water, overnight and then killed under ether anesthesia by exsanguination from the aorta. Peripheral blood was taken from each mouse for the microscopical examination by Giemsa stain.Gross findings were recorded and the following organs of each mouse were weighed: brain, heart, lung, liver, pancreas, spleen, kidney, adrenals, and testes or ovaries. Samples of these organs and of salivary gland, trachea, thymus, lymph nodes, stomach, small intestine, large intestine, urinary bladder, pituitary, thyroid, prostate, seminal vesicle, uterus, vagina, mammary gland, skeletal muscle, eye, Harderian glands, spinal cord, bone (sternal bone, ribs, vertebral bone), and other tissues with abnormal appearance were fixed in 10 % neutralized formalin. Preserved tissues to be examined microscopically were embedded in paraffin wax, sectioned, and stained with hematoxylin and eosin (HE).Histopathological examinations were also performed on mice found dead and those in moribund condition when killed.
Statistics:
Data on cumulative mortality and tumor incidence were analyzed for statistical significance by the chi-square test.
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
- Final body weights of female and male mice showed no significant differences among each group.- Throughout the study, the rate of water consumption by female mice in any group treated with sodium chlorite showed no consistent deviation from the control. On the other hand, water consumption by male mice treated with a high dose of sodium chlorite was slightly lower than the other groups. For treated groups, total intakes of sodium chlorite for 80 weeks, calculated from mean water consumption collected on 46 different days during the study for a mouse from each group, were 658 and 1067 mg/mouse in the low dose group, and 1261 and 1606 mg/mouse in the high dose group for females and males, respectively.- There was no dose-related trend in mortality over the experimental period in the control and other treated groups for females and males.- No significant increases with dose dependency were seen in any organ weight and percent organ to body weight ratio of both females and males treated with sodium chlorite compared to control groups.- Nonneoplastic lesions in various organs were infrequent, and no significant differences in the incidence between control and treated groups were íound.- The incidence of tumor-bearing animals was 32% (control), 34% (low dose), and 26% (high dose) in female mice, and 46% (control), 57% (low dose), and 53% (high dose) in male mice. The types and incidence of neoplasms that occurred frequently in each group of both sexes were similar to those observed spontaneously in B6C3F1 mice. The incidence of lymphomas/leukemias in the high dose group of females (2%), however, was lower than that in the control group (15%). Furthermore, the incidence of pulmonary adenomas in the high dose group of males (12%) was higher than that in the control group (0%), but neither dose-related increases in the adenoma incidences nor increased incidences of the adenocarcinomas were observed.
Relevance of carcinogenic effects / potential:
These results indicated no clear evidence of a carcinogenic potential of sodium chlorite in B6C3F1 mice.
Key result
Dose descriptor:
NOEL
Effect level:
>= 83 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: carcinogenicity
Key result
Dose descriptor:
NOEL
Effect level:
>= 58 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: carcinogenicity

Table 1. Final body weights and organ weights of B6C3F1 mice given sodium chlorite in drinking water.

Dose, %

Sex

No. of mice examined

Body weight, g

Organ weight, g (% of body weight)

Initial

Final

Lung

Liver

Pancreas

Kidney

Spleen

Heart

Brain

0

 

 

 

F

47

 

20.0 ± 1.0

48.4 ± 3.7

0.36 ± 0.21

1.54 ± 0.34

0.33 ± 0.07

0.46 ± 0.27

0.17 ±0.19

0.13 ± 0.03

0.44 ± 0.03

 

 

(0.71)

(3.18)

(0.68)

(0.95)

(0.35)

(0.27)

(0.91)

M

35

 

25.6 ± 1.1

40.3 ± 2.5

0.40 ± 0.10

1.95 ± 0.73

0.43 ± 0.81

0.67 ± 0.10

0.18 ± 0.27

0.21 ± 0.05

0.46 ± 0.05

 

 

(0.99)

(4.8)

(1.07)

(1.66)

(0.45)

(0.52)

(1.14)

0.025

 

 

 

F

50

 

19.9 ± 0.3

50.8 ± 2.5

0.44 ±0.13

1.70 ± 0.42

0.38 ±0.14

0.48 ± 0.09

0.24 ± 0.54

0.17 ± 0.03

0.46 ± 0.03

 

 

(0.87)

(3.35)

(0.75)

(0.94)

(0.47)

(0.33)

(0.91)

M

50

 

25.5 ± 0.6

40.3 ± 2.0

0.38 ± 0.07

2.06 ± 1.12

0.36 ±0.10

0.65 ± 0.08

0.13 ±0.10

0.21 ± 0.03

0.44 ± 0.05

 

 

(0.94)

(5.11)

(0.89)

(1.61)

(0.32)

(0.52)

(1.09)

0.05

 

 

 

F

50

 

19.4 ± 0.4

47.4 ± 3.9

0.38 ± 0.09

1.58 ± 0.49

0.37 ± 0.44

0.45 ± 0.06

0.25 ± 0.41

0.15 ± 0.03

0.44 ± 0.05

 

 

(0.80)

(3.33)

(0.78)

(0.95)

(0.53)

(0.31)

(0.93)

M

50

 

26.0 ±0.1

42.7 ± 1.2

0.43 ± 0.15

2.33 ± 1.28

0.40 ± 0.12

0.66 ± 0.09

0.16 ±0.16

0.21 ± 0.03

0.43 ± 0.05

 

 

(1.10)

(5.47)

(0.94)

(1.55)

(0.37)

(0.49)

(1.01)

a Values represent average ± SD.

Conclusions:
The incidence of tumor-bearing animals was 32% (control), 34% (low dose), and 26% (high dose) in female mice, and 46% (control), 57% (low dose), and 53% (high dose) in male mice. The types and incidence of neoplasms that occurred frequently in each group of both sexes were similar to those observed spontaneously in B6C3F1 mice. The incidence of lymphomas/leukemias in the high dose group of females (2%), however, was lower than that in the control group (15%). Furthermore, the incidence of pulmonary adenomas in the high dose group of males (12%) was higher than that in the control group (0%), but neither dose-related increases in the adenoma incidences nor increased incidences of the adenocarcinomas were observed.
Executive summary:

The carcinogenic activity of sodium chlorite in B6C3F1 mice was examined with a method similar to OECD guideline 451. Sodium chlorite was given at concentrations of 0 (control), 0.025% (low dose), or 0.05% (high dose) in the drinking water of 150 female and 150 male mice for 80 weeks, after which time the animals were returned to distilled water without sodium chlorite. The withdrawal may further progress the induced tumor growth or regress reversible proliferative lesions, which makes a histological evaluation of test compounds easier. All mice were sacrificed 85 weeks from the beginning of the experiment.

The incidence of tumor-bearing animals was 32% (control), 34% (low dose), and 26% (high dose) in female mice, and 46% (control), 57% (low dose), and 53% (high dose) in male mice. The types and incidence of neoplasms that occurred frequently in each group of both sexes were similar to those observed spontaneously in B6C3F1 mice. The incidence of lymphomas/leukemias in the high dose group of females (2%), however, was lower than that in the control group (15%). Furthermore, the incidence of pulmonary adenomas in the high dose group of males (12%) was higher than that in the control group (0%), but neither dose-related increases in the adenoma incidences nor increased incidences of the adenocarcinomas were observed.

These results indicated no clear evidence of a carcinogenic potential of sodium chlorite in B6C3F1 mice.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
other: rats and mice
Quality of whole database:
Weight of evidence: experimental results: oral studies with rats and mice by administration in drinking water (for 80 or 85 weeks) and dermal studies with female mice (for 51 weeks). Under these conditions, there was no evidence of carcinogenic activity for sodium chlorite in rats and mice.

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Test method was not according to any guideline. Promoting studies. No data on GLP.
Principles of method if other than guideline:
Sodium chlorite was tested for tumor-promoting activity in skin carcinogenesis using female Sencar mice. Test substance was applied twice a week for 51 weeks after initiation with dimethylbenzanthracene (DMBA). Sodium chlorite was dissolved in acetone and 0.2 mL was applied to the dorsal skin by automatic pipette (20 mg/mL). The number and diameter of all skin tumors were recorded weekly and body weight was measured monthly. At autopsy, the skin and major organs were fixed in 10 % buffered formalin and stained with hematoxylin and eosin. Data were analyzed statistically by Fisher's exact probability test and/or the chi-square test.
GLP compliance:
not specified
Species:
mouse
Strain:
Sencar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Shizuoka Laboratory Center, Shizuoka.
- Age at study initiation: 4 weeks old.
- Housing: Mice were housed, 5 to a plastic hanging cage, with sterilized softwood chips as bedding in a barrier-sustained animal room.
- Diet (e.g. ad libitum): Food was given ad libitum.
- Water (e.g. ad libitum): Water was given ad libitum.
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 1 ºC
- Humidity (%): 55 ± 5 %
Route of administration:
dermal
Vehicle:
acetone
Details on exposure:
- Dorsal skin of the mice was shaved 48 h before treatment with surgical clippers.- The mice received a single topical application of 20 nmol of DMBA (dimethylbenzanthracene) in 0.2 mL of acetone or acetone only, followed 1 week later by application of the test substance, TPA or acetone for 51 weeks.- Sodium chlorite was dissolved in acetone and 0.2 mL was applied to the dorsal skin by automatic pipette.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
51 weeks
Frequency of treatment:
Twice weekly.
Post exposure period:
The back of the mice was shaved once a week.
Dose / conc.:
20 other: mg/mL
No. of animals per sex per dose:
20 female mice in the treated and the positive control groups.15 female mice were used in the vehicle control group.
Control animals:
yes, concurrent vehicle
Details on study design:
The dose for the experiment was determined on the basis of a subacute skin toxicity test for 4 weeks.
Positive control:
12-O-tetradecanoyl-phorbol-13-acetate (TPA), 10 µg/mL.
Observations and examinations performed and frequency:
The number and diameter of all skin tumors were recorded weekly and body weight was measured monthly.
Sacrifice and pathology:
At autopsy, the skin and major organs were fixed in 10 % buffered formalin and stained with hematoxylin and eosin.At necropsy, organs were grossly examined, excised, and weighed. They were stained with hematoxylin and eosin after routine histological processing.
Statistics:
Data were analyzed statistically by Fisher's exact probability test and/or the chi-square test.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
If a body weight of 20 g is assumed, the dose would be equivalent to 400 mg sodium chlorite/kg bw per week (57.14 mg/kg bw per day).Although statistically not significant, 30 % of the mice treated with sodium chlorite developed skin tumors and 5 out of these 6 mice had squamous cell carcinomas. In this group, the first skin tumor appeared in week 17.All the mice treated with TP A after initiation with DMBA as positive controls developed squamous cell carcinomas within 39 weeks.On the other hand, control mice applied with acetone after DMBA-initiation had no skin tumors.The relatively high incidences of adenocarcinomas of the mammary gland and adenomas of the lung and the uterus were observed in all groups.There were no significant differences in the mean survival times and body weights of the mice treated with the chemical other than TP A in this test.
Relevance of carcinogenic effects / potential:
Potential promoting effect was suspected in sodium chlorite.
Key result
Dose descriptor:
NOEL
Effect level:
>= 57.14 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: skin carcinogenesis

Potential promoting effect was suspected in sodium chlorite.

Conclusions:
Although statistically not significant, 30 % of the mice treated with sodium chlorite developed skin tumors and 5 out of these 6 mice had squamous cell carcinomas. In this group, the first skin tumor appeared in week 17.
Executive summary:

Sodium chlorite was tested for tumor-promoting activity in skin carcinogenesis using female Sencar mice. Test substance was applied twice a week for 51 weeks after initiation with dimethylbenzanthracene (DMBA). Sodium chlorite was dissolved in acetone and 0.2 mL was applied to the dorsal skin by automatic pipette (20 mg/mL). The number and diameter of all skin tumors were recorded weekly and body weight was measured monthly. At autopsy, the skin and major organs were fixed in 10 % buffered formalin and stained with hematoxylin and eosin. Data were analyzed statistically by Fisher's exact probability test and/or the chi-square test.

Although statistically not significant, 30 % of the mice treated with sodium chlorite developed skin tumors and 5 out of these 6 mice had squamous cell carcinomas. In this group, the first skin tumor appeared in week 17.

Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Test method was not according to any guideline. Promoting studies. No data on GLP.
Principles of method if other than guideline:
Sodium chlorite was tested for complete carcinogenic activity in skin carcinogenesis using female Sencar mice. Test substance was applied twice a week for 51 weeks. Sodium chlorite was dissolved in acetone and 0.2 mL was applied to the dorsal skin by automatic pipette (20 mg/mL). The number and diameter of all skin tumors were recorded weekly and body weight was measured monthly. At autopsy, the skin and major organs were fixed in 10 % buffered formalin and stained with hematoxylin and eosin. Data were analyzed statistically by Fisher's exact probability test and/or the chi-square test.
GLP compliance:
not specified
Species:
mouse
Strain:
Sencar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Shizuoka Laboratory Center, Shizuoka.
- Age at study initiation: 4 weeks old.- Housing: Mice were housed, 5 to a plastic hanging cage, with sterilized softwood chips as bedding in a barrier-sustained animal room.
- Diet (e.g. ad libitum): Food was given ad libitum.
- Water (e.g. ad libitum): Water was given ad libitum.
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 1 ºC
- Humidity (%): 55 ± 5 %
Route of administration:
dermal
Vehicle:
acetone
Details on exposure:
- Dorsal skin of the mice was shaved 48 h before treatment with surgical clippers.- Sodium chlorite was dissolved in acetone and 0.2 mL was applied to the dorsal skin by automatic pipette.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
51 weeks
Frequency of treatment:
Twice weekly.
Post exposure period:
The back of the mice was shaved once a week.
Dose / conc.:
20 other: mg/mL
No. of animals per sex per dose:
20 female mice in the treated group.15 female mice were used in the vehicle control group.
Control animals:
yes, concurrent vehicle
Details on study design:
The dose for the experiment was determined on the basis of a subacute skin toxicity test for 4 weeks.
Observations and examinations performed and frequency:
The number and diameter of all skin tumors were recorded weekly and body weight was measured monthly.
Sacrifice and pathology:
At autopsy, the skin and major organs were fixed in 10 % buffered formalin and stained with hematoxylin and eosin.
Statistics:
Data were analyzed statistically by Fisher's exact probability test and/or the chi-square test.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
If a body weight of 20 g is assumed, the dose would be equivalent to 400 mg sodium chlorite/kg bw per week (57.14 mg/kg bw per day).No skin tumors developed in the mice applied with sodium chlorite or acetone (vehicle).The relatively high incidences of adenocarcinomas of the mammary gland and adenomas of the lung and the uterus were observed in all groups.There were no significant differences in the mean survival times and body weights of the mice treated with the chemical other than TP A in this test.
Relevance of carcinogenic effects / potential:
It was inactive as a skin carcinogen.
Key result
Dose descriptor:
NOEL
Effect level:
>= 57.14 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: skin carcinogenesis

It was inactive as a skin carcinogen.

Conclusions:
No skin tumors developed in the mice applied with sodium chlorite or acetone (vehicle).
Executive summary:

Sodium chlorite was tested for complete carcinogenic activity in skin carcinogenesis using female Sencar mice.Test substance was applied twice a week for 51 weeks. Sodium chlorite was dissolved in acetone and 0.2 mL was applied to the dorsal skin by automatic pipette (20 mg/mL). The number and diameter of all skin tumors were recorded weekly and body weight was measured monthly. At autopsy, the skin and major organs were fixed in 10 % buffered formalin and stained with hematoxylin and eosin. No skin tumors developed in the mice applied with sodium chlorite or acetone (vehicle).It was inactive as a skin carcinogen.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
mouse
Quality of whole database:
Weight of evidence: experimental results: oral studies with rats and mice by administration in drinking water (for 80 or 85 weeks) and dermal studies with female mice (for 51 weeks). Under these conditions, there was no evidence of carcinogenic activity for sodium chlorite in rats and mice.

Additional information

Weight of evidence: Experimental results:

In the first publication, groups of 50 male and 50 female B6C3F1 mice were dosed with sodium chlorite in the drinking-water at concentrations of 0, 250 or 500 mg/L for 80 weeks followed by distilled water alone for 5 weeks.

In the second publication, groups of 50 rats and mice of each sex were administered sodium chlorite in the drinking water for 85 weeks. Rats were treated with concentrations of 0, 300 or 600 ppm; and mice with concentrations of 0, 250 or 500 ppm.

In the third publication, a study of carcinogenicity and tumour-promoting effects, 0.2 mL sodium chlorite solution dissolved in acetone (20 mg/mL) was applied twice weekly to the shaven skin of 15–20 female Sencar mice for 51 weeks with and without prior initiation by topical application of 20 nmol dimethylbenzanthracene (DMBA).

In the last publication, Sodium chlorite was administered at concentrations of 0, 300 or 600 mg/L in drinking-water to groups of 50 male and 50 female F344 rats for 85 weeks, when the study was prematurely terminated because of widespread infection with Sendai virus.

None of these studies showed any evidence of carcinogenic activity for sodium chlorite in rats and mice.


Justification for classification or non-classification

Based on the available results, the substance sodium chlorite is not classified for carcinogenicity.