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Carcinogenicity

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Description of key information

In mice, NOAEL in males is 2000 mg/l in drinking water, whereas for females this is 1000 mg/l, also based on thyroid follicular cell hypertrophy. This corresponds to 60 mg/kg bw/day in females and 80 mg/kg bw/day in males. There was a marginally increased incidence (positive trend) of pancreatic island neoplasms observed in females although the authors considered these results to be equivocal. The effect was only observed in only one sex, the incidences for either adenomas or adenomas and carcinomas (combined) were not statistically significant [the global incidence of hyperplasia plus adenomas remains flat over dose (9/46; 8/47; 6/49; 6/49).] Similar effects were not observed in the rat carcinogenicity study. In the rat the NOAEL for tumourigenic effects on thyroid is 1000 mg/l in drinking water, equivalent to 35 mg/kg bw/day in males and 45 mg/kg bw/day in females. For non-neoplastic effects, the effects on the thyroid are the most critical. The seriousness of the long term TSH stimulation of the follicle cells is relatively limited as only hypertrophy and not hyperplasia were observed even at the two highest doses of sodium chlorate at the end of the 13 week study. In the 2-year study positive trends were observed in the incidences of thyroid gland follicular cell adenoma or carcinoma (combined) in males and females. At 125 mg/l, only at the end of the 2-year study a minimal increase in follicular cell hypertrophy has been observed in males.

The NOAEL for tumorigenic effects on thyroid is 1000 mg/L, equivalent to 35 mg/kg bw/day in males and 45 mg/kg bw/day in females.

For non neoplastic effects, based on thyroid follicular cell hypertrophy, the LOAEL in males is 125 mg/l that corresponds to 5 mg/kg bw/day. As this was the only effect observed, clinically of marginal relevance, and caused by a physiological compensatory mechanism, this could also be the NOAEL.

NOAEL in females is 125 mg/l (equivalent to 5 mg/kg bw/day) based also on thyroid follicular cell hypertrophy.

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:
key study
Study period:
September 1998 - September 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was performed under GLP and according to methods equivalent or similar to internationally accepted guidelines.
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPPTS 870.4200 (Carcinogenicity)
GLP compliance:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Taconic Laboratory Animals and Services (Germantown, NY)
- Age at study initiation: 6 weeks
- Weight at study initiation: in week 1 males weighed ± 102g and females weighed ± 91g
- Fasting period before study: Not applicable
- Housing: Rats: 3 (males) or 5 (females) per cage. Solid-bottom polycarbonate (Lab Products, Maywood, NJ), changed twice weekly (rats and female mice) or weekly (male mice) with bedding
Irradiated hardwood chips (mice) or heat-treated irradiated hardwood chips (rats) (P.J. Murphy Forest Products Corp., Montville, NJ), twice weekly.
- Diet (e.g. ad libitum): NTP-2000 irradiated pelleted diet (Zeigler Brothers, Inc., Gardners, PA), available ad libitum, changed weekly
- Water (e.g. ad libitum): Tap water (Birmingham municipal supply) via amber glass water bottles with stainless steel screw caps (Kerr Glass Manufacturing Corp., Plainfield, IL), available ad libitum, changed twice weekly
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2 ± 1.6
- Humidity (%): 50 ± 15
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 16 September 1998 to 13-21 September 2000
Route of administration:
oral: drinking water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The dose formulations were prepared every 4 weeks during the 2-year studies by mixing sodium chlorate with tap water. Homogeneity studies of 125 and 2,000 mg/L dose formulations were performed by the study laboratory using IC. Stability studies of a 2 mg/L dose formulation were performed by the analytical chemistry laboratory using IC. Homogeneity was confirmed.
Stability was confirmed for at least 44 days for dose formulations stored in sealed NALGENE® containers at temperatures up to 25° C and for at least 7 days when stored in drinking water bottles under simulated animal room conditions.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Periodic analyses of the dose formulations of sodium chlorate were conducted by the study laboratory using IC. During the 2-year studies, the dose
formulations were analyzed approximately every 10 weeks. Of the dose formulations used, 40 of 42 were within 10% of the target concentrations.
Duration of treatment / exposure:
main study: 105 - 106 weeks
special study: up to 14 weeks
Frequency of treatment:
daily 7/7
Post exposure period:
None
Remarks:
Doses / Concentrations:
125, 1000 or 2000 mg/l for 104 weeks. The achieved dosages averaged 5, 35 and 75 mg/kg bw/day for males and 5, 45 and 95 mg/kg bw/day for females.
Basis:
nominal in water
No. of animals per sex per dose:
Main test group: 50
Special test group for thyroid hormone evaluations and histopathology: 20
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Because there were no effects of sodium chlorate on survival or body weights of male or female F344/N rats in 3 week studies, the highest exposure concentration selected for the 2-year study was 2,000 mg/L. Although follicular cell hypertrophy was observed at 1,000 and 2,000 mg/L, it was not considered a potential threat to the health of the rats during a 2-year study. A low dose of 125 mg/L was selected because it was anticipated to be a no-observed-adverse-effect level for thyroid gland effects.
- Rationale for animal assignment (if not random): Animals were distributed randomly into groups of approximately equal initial mean body weights.
- Rationale for selecting satellite groups: Additional groups of 20 male and 20 female special study rats were exposed to the same concentrations for up to 14 weeks for thyroid hormone evaluations and histopathology. Groups of 50 male and 50 female rats were exposed to drinking water containing 0, 500, 1,000, or 2,000 mg/L sodium chlorate for 105 to 106 weeks.
- Post-exposure recovery period in satellite groups: none
- Section schedule rationale (if not random): not specified
Positive control:
Not applicable
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observed twice daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical findings were recorded every 4 weeks.

BODY WEIGHT: Yes
- Time schedule for examinations: Core study animals were weighed initially, every 4 weeks, and at the end of the studies.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Water consumption by cage was recorded every 4 weeks.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood was collected from the retroorbital sinus of special study rats on day 4 and from all core study animals at the end of the studies.
- Anaesthetic used for blood collection: Yes; Rats were anesthetized with CO2/O2 for each blood collection. Special study rats bled at week 3 or week 14 were sacrificed and necropsied. Core study animals were sacrificed and necropsied. Method of sacrifice: Carbon dioxide asphyxiation.
- Animals fasted: No data
- How many animals: all animals.
- Parameters examined: hematocrit; hemoglobin concentration; erythrocyte, reticulocyte, and platelet counts; erythrocyte morphology; mean cell
volume; mean cell hemoglobin; mean cell hemoglobin concentration; and leukocyte count and differentials

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood was collected from the retroorbital sinus of special study rats on day 4 and from all core study animals at the end of the studies.
Also at 4 days, 3 weeks, and 14 weeks, blood was collected from the retroorbital sinus of special 10 study male and female rats per group for determinations of thyroid stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4).
- Animals fasted: No data
- How many animals: 10 special study rats and all core study animals.
- Parameters examined: urea nitrogen, creatinine, total protein, albumin, alanine aminotransferase, alkaline phosphatase, creatine kinase, sorbitol dehydrogenase, bile acids, thyroid stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4).

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Complete histopathology was performed on all core study rats.
In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone with marrow, brain, clitoral gland, esophagus, gallbladder (mice), harderian gland, heart and aorta, 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, seminal vesicle, skin, spleen, stomach (forestomach and glandular), testis (with epididymis), thymus, thyroid gland, trachea, urinary bladder, and uterus.
In addition, the thyroid gland of special study rats was examined at 3 and 14 weeks.
Other examinations:
None
Statistics:
See "any other information on materials....."
Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Description (incidence):
According to statistical analysis (Kaplan-meier survival curves) the survival of exposed rats was similar to that of the control group. The reason of death for these animals is described in the table below, accidental, mordibund or natural death.

Male 0 mg/l 125 mg/l 1000 mg/l 2000 mg/l
Accidental death 1 0 0 0
Moribund 10 13 11 14
Natural deaths 3 10 8 8

Female 0 mg/l 125 mg/l 1000 mg/l 2000 mg/l
Moribund 10 11 11 4
Natural deaths 3 3 6 5
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The mean body weights of all exposed groups were similar to those of the control groups throughout the study.
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
Description (incidence and severity):
Water consumption by exposed rats was generally similar to that by controls throughout the study (see tables below). Drinking water concentrations of 125, 1,000, and 2,000 mg/L resulted in average daily doses of approximately 5, 35, and 75 mg/kg per day for male rats and 5, 45, and 95 mg/kg
per day for female rats.

Mean water consumption for weeks in g at the different dose levels.
Male
0 mg/l 125 mg/l 1000 mg/l 2000 mg/l
1-4 16.1 16.4 16.6 17.1
14-52 14.3 14.5 14.6 15.0
53-104 14.9 15.3 15.4 16.0

Female
0 mg/l 125 mg/l 1000 mg/l 2000 mg/l
1-4 12.1 12.5 12.4 12.3
14-52 10.6 11.1 10.7 10.9
53-104 12.6 12.7 13.0 13.2
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Assays for thyroxine (T4), triiodothyronine (T3), and thyroid stimulating hormone (TSH) were conducted using special study rats on day 4, at week 3, and at week 14. Serum concentrations of T4 and T3 were significantly reduced in 1,000 and 2,000 mg/L males and females on day 4 and in 2,000 mg/L males and females at week 3. Serum concentrations of TSH generally increased with exposure concentration and were significantly increased in 1,000 and 2,000 mg/L males on day 4 and at week 3, in 1,000 and 2,000 mg/L females on day 4, in 2,000 mg/L females at week 3, and in 2,000 mg/L males and females at week 14.
See table 1 in "Overall remarks...."
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Thyroid gland:
Slightly enlarged thyroid glands were observed in 1,000 and 2,000 mg/L special study male rats and 2,000 mg/L special study female rats at 14 weeks.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Thyroid gland:
All special study rats in the 1,000 and 2,000 mg/L groups had follicular cell hypertrophy at 3 and 14 weeks; this lesion did not occur in control rats.
The incidences of follicular cell hypertrophy in all exposed groups of males and in 1,000 and 2,000 mg/L females at 2 years were significantly greater than those in the control groups and the severity was increased in 2,000 mg/L males and females. Histologically, the normal thyroid gland is composed of variably-sized follicles containing eosinophilic material (colloid) within the lumens. These follicles range in size from very small (approximately 50 microns) containing little colloid to relatively large (several hundred microns) filled with colloid. In smaller follicles, the epithelium is generally cuboidal, while more attenuated in glands distended with colloid. Following sodium chlorate administration, there was an exposure concentration-related increase in the percentage of smaller follicles, and these follicles contained sparse amounts of generally pale, often vacuolated appearing colloid (colloid depletion). The lining epithelium of affected glands appeared more prominent, ranging from cuboidal to somewhat columnar.
See table 2 in "Overall remarks...."

Spleen:
The incidence of hematopoietic cell proliferation was significantly increased in 2,000 mg/L males when compared to the control group (0 mg/L, 2/48, severity grade 2.5; 125 mg/L, 6/49, severity grade 2.3; 1,000 mg/L, 4/49, severity grade 2.5; 2,000 mg/L, 11/50, severity grade 2.5). Histologically, this lesion was characterized by an increase in erythroid and myeloid cells within the red pulp. While the increase in hematopoietic cell proliferation was modest and not observed in the 3-week study, this finding is consistent with hematological effects observed in humans and other animal species administered sodium chlorate.

Bone Marrow:
The incidences of bone marrow hyperplasia were significantly increased in 1,000 and 2,000 mg/L males when compared to the control group (0 mg/L, 28/48; 125 mg/L, 35/48; 1,000 mg/L, 41/50; 2,000 mg/L, 40/49). The severity grades of this lesion were greater in all treatment groups when compared to controls (1.9, 2.3, 2.4, 2.7). Microscopically, bone marrow hyperplasia was characterized by an increase of hematopoietic cells in the marrow cavity. Though histological evaluation of bone marrow sections is generally a crude assessment of erythroid and/or myeloid response, the increases in hyperplasia incidence and severity suggest this was a treatment-related effect.
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Thyroid gland:
There were positive trends in the incidences of follicular cell carcinoma in male rats and in follicular cell adenoma or carcinoma (combined) in males and females. The incidences of follicular cell adenoma, follicular cell carcinoma, and follicular cell adenoma or carcinoma (combined) in 2,000 mg/L males and females exceeded the historical ranges for drinking water controls.

Microscopically, adenomas were well demarcated, focal, expansile masses consisting of well-differentiated thyroid follicular epithelial cells forming follicular structures with central colloid. Increased cell density occasionally led to the formation of papillary projections into the lumens of the follicle. Histologically, carcinomas were less well demarcated and less well differentiated and consisted of glandular to solid hypercellular masses of pleomorphic thyroid epithelial cells.Occasionally, invasion into the peripheral thyroid was noted.

The incidences of focal follicle mineralization in 1,000 and 2,000 mg/L females were significantly greater than that in the control group, and the severity was increased in the 2,000 mg/L group. This lesion consisted of basophilic, ovoid-shaped bodies in the colloid of some of the thyroid follicles. This is a common aging change, but the increased incidences may have been exacerbated by exposure to sodium chlorate.
See table 3. "Overall remarks...."

Mononuclear Cell Leukemia:
The incidence of mononuclear cell leukemia was significantly increased in the male 2,000 mg/L group when compared to controls (13/50, 21/50, 16/50, 23/50). However, the incidences of this lesion in all exposed groups fell within the historical range in controls (all routes) [514/1,159 (43.1% ± 12.8%), range 22% to 68%]. Because the incidence of mononuclear cell leukemia in the control group was at the low end of the historical control range and near average in the exposed groups, this lesion was not attributed to sodium chlorate administration.
Details on results:
HISTORICAL CONTROL DATA
For the observed effects a comparison was made with historical control data. The concurrent control group represents the most valid comparison to the treated groups and is the only control group analyzed statistically in NTP bioassays. However, historical control data are often helpful in interpreting potential treatment-related effects, particularly for uncommon or rare neoplasm types.
Relevance of carcinogenic effects / potential:
See "Attached document" for position paper on the relevance of these finding for humans.
Dose descriptor:
NOAEL
Effect level:
35 mg/kg bw/day
Sex:
male
Basis for effect level:
other: Thyroid gland follicular cell carcinoma or adenoma
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
45 mg/kg bw/day
Sex:
female
Basis for effect level:
other: Thyroid gland follicular cell carcinoma or adenoma
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
LOAEL
Effect level:
5 mg/kg bw/day
Sex:
male
Basis for effect level:
other: Thyroid gland follicular cell hyperthrophy
Remarks on result:
other: Effect type: toxicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day
Sex:
female
Basis for effect level:
other: Thyroid gland follicular cell hyperthrophy
Remarks on result:
other: Effect type: toxicity (migrated information)
Conclusions:
The NTP concludes that under the conditions of this 2-year drinking water study “there was some evidence of carcinogenic activity of sodium chlorate in male and female F344/N rats based on increased incidences of thyroid gland neoplasms. There was no evidence of carcinogenic activity of sodium chlorate in male B6CF3F1 mice exposed to 500, 1,000, or 2,000 mg/l. There was equivocal evidence of carcinogenic activity of sodium chlorate in female B6CF3F1 mice based on marginally increased incidence of pancreatic island neoplasms.”
Executive summary:

Under GLP and according to methods equivalent to internationally accepted guidelines groups of 50 male and 50 female rats were exposed to drinking water containing 0, 125, 1,000, or 2,000 mg/L sodium chlorate for 2 years (equivalent to average daily doses of approximately 5, 35, and 75 mg/kg per day for male rats and 5, 45, and 95 mg/kg per day for female rats).

Survival of exposed rats was similar to that of the control groups. Mean body weights of all exposed groups were similar to those of the control groups throughout the study. Water consumption by exposed rats was generally similar to that by controls throughout the study. Serum concentrations of thyroxine and triiodothyronine were significantly reduced in 1,000 and 2,000 mg/L males and females on day 4 and in 2,000 mg/L males and females at week 3. Serum concentrations of thyroid stimulating hormone were significantly increased in 1,000 and 2,000 mg/L males on day 4 and at week 3, in 1,000 and 2,000 mg/L females on day 4, in 2,000 mg/L females at week 3, and in 2,000 mg/L males and females at week 14. All special study rats in the 1,000 and 2,000 mg/L groups had thyroid gland follicular cell hypertrophy at 3 and 14 weeks. There were positive trends in the incidences of thyroid gland follicular cell carcinoma in male rats and of thyroid gland follicular cell adenoma or carcinoma (combined) in males and females. The incidences of thyroid gland follicular cell hypertrophy were significantly increased in all exposed groups of males and in 1,000 and 2,000 mg/L females. Thyroid gland focal follicle mineralization occurred in most 1,000 and 2,000 mg/L female rats. The incidences of hematopoietic cell proliferation in the spleen of 2,000 mg/L males and bone marrow hyperplasia in 1,000 and 2,000 mg/L males were significantly greater than those in the controls.

The NTP concludes that under the conditions of this 2-year drinking water study, there was some evidence of carcinogenic activity of sodium chlorate in male and female F344/N rats based on increased incidences of thyroid gland neoplasms.

Exposure to sodium chlorate resulted in non-neoplastic lesions in the thyroid gland of male and female rats, bone marrow of male rats, and spleen of male rats.

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
September 1998 - September 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was performed under GLP and according to methods equivalent or similar to internationally accepted guidelines.
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPPTS 870.4200 (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 Laboratory Animals and Services (Germantown, NY)
- Age at study initiation: 6 weeks
- Weight at study initiation: in week 1 males weighed ± 22g and females weighed ± 18g
- Fasting period before study: Not applicable
- Housing: 1 (males) or 5 (females) per cage. Solid-bottom polycarbonate (Lab Products, Maywood, NJ), changed twice weekly (rats and female mice) or weekly (male mice) with bedding
Irradiated hardwood chips (mice) or heat-treated irradiated hardwood chips (rats) (P.J. Murphy Forest Products Corp., Montville, NJ), twice weekly.
- Diet (e.g. ad libitum): NTP-2000 irradiated pelleted diet (Zeigler Brothers, Inc., Gardners, PA), available ad libitum, changed weekly
- Water (e.g. ad libitum): Tap water (Birmingham municipal supply) via amber glass water bottles with stainless steel screw caps (Kerr Glass Manufacturing Corp., Plainfield, IL), available ad libitum, changed twice weekly
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2 ± 1.6
- Humidity (%): 50 ± 15
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 30 September 1998 to 27 September-5 October 2000
Route of administration:
oral: drinking water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The dose formulations were prepared every 4 weeks during the 2-year studies by mixing sodium chlorate with tap water. Homogeneity studies of 125 and 2,000 mg/L dose formulations were performed by the study laboratory using IC. Stability studies of a 2 mg/L dose formulation were performed by the analytical chemistry laboratory using IC. Homogeneity was confirmed.
Stability was confirmed for at least 44 days for dose formulations stored in sealed NALGENE® containers at temperatures up to 25° C and for at least 7 days when stored in drinking water bottles under simulated animal room conditions.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Periodic analyses of the dose formulations of sodium chlorate were conducted by the study laboratory using IC. During the 2-year studies, the dose
formulations were analyzed approximately every 10 weeks. Of the dose formulations used, 40 of 42 were within 10% of the target concentrations.
Duration of treatment / exposure:
105 - 106 weeks
Frequency of treatment:
daily 7/7
Post exposure period:
None
Remarks:
Doses / Concentrations:
500, 1000 or 2000 mg/l for 104 weeks. Resulting in verage daily doses of approximately 40, 80, and 160 mg/kg per day for male mice and 30, 60, and 120 mg/kg per day for female mice.
Basis:
nominal in water
No. of animals per sex per dose:
Main test group: 50
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
Because sodium chlorate produced no biologically significant changes in any of the parameters examined in male or female B6C3F1 mice, exposure concentrations of 500, 1,000, and 2,000 mg/L were selected for the 2-year study in B6C3F1 mice.
- Rationale for animal assignment (if not random): Animals were distributed randomly into groups of approximately equal initial mean body weights.
- Rationale for selecting satellite groups: Groups of 50 male and 50 female mice were exposed to drinking water containing 0, 500, 1,000, or 2,000 mg/L sodium chlorate for 105 to 106 weeks.
- Post-exposure recovery period in satellite groups: none
- Section schedule rationale (if not random): not specified
Positive control:
Not applicable
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observed twice daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical findings were recorded every 4 weeks.

BODY WEIGHT: Yes
- Time schedule for examinations: Core study animals were weighed initially, every 4 weeks, and at the end of the studies.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Water consumption by cage was recorded every 4 weeks.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood was collected from the retroorbital sinus from all core study animals at the end of the studies.
- Anaesthetic used for blood collection: Yes; anesthetized with CO2/O2 for each blood collection. Core study animals were sacrificed and necropsied. Method of sacrifice: Carbon dioxide asphyxiation.
- Animals fasted: No data
- How many animals: all animals.
- Parameters examined: hematocrit; hemoglobin concentration; erythrocyte, reticulocyte, and platelet counts; erythrocyte morphology; mean cell
volume; mean cell hemoglobin; mean cell hemoglobin concentration; and leukocyte count and differentials

CLINICAL CHEMISTRY: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Complete histopathology was performed on all core study mice.
In addition to gross lesions and tissue masses, the following tissues were examined: adrenal gland, bone with marrow, brain, clitoral gland, esophagus, gallbladder (mice), harderian gland, heart and aorta, 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, seminal vesicle, skin, spleen, stomach (forestomach and glandular), testis (with epididymis), thymus, thyroid gland, trachea, urinary bladder, and uterus.
Other examinations:
None
Statistics:
See "any other information on materials....."
Clinical signs:
no effects observed
Description (incidence and severity):
No clinical findings related to sodium chlorate exposure were observed.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Survival of exposed mice was similar to that of the control groups.
Male 0 mg/l 125 mg/l 1000 mg/l 2000 mg/l
Moribund 5 5 4 10
Natural deaths 7 4 5 7
Female 0 mg/l 125 mg/l 1000 mg/l 2000 mg/l
Acidental death 1 0 0 0
Other 0 0 1 0
Moribund 3 5 6 8
Natural deaths 10 10 12 7
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
The mean body weights of exposed groups of males were similar to those of the control group through out the study. The body weight of the females mice were generally less than that of the control group from week 84.
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
Description (incidence and severity):
Water consumption by exposed mice was generally similar to that by controls throughout the study. Mean water consumption for weeks in g at the different dose levels:
Male 0 mg/l 125 mg/l 1000 mg/l 2000 mg/l
1-4 3.4 3.6 3.4 3.5
14-52 3.5 3.4 3.4 3.4
53-104 4.2 4.1 4.1 4.0
Female 0 mg/l 125 mg/l 1000 mg/l 2000 mg/l
1-4 3.2 3.2 3.2 3.6
14-52 2.5 2.5 2.5 2.6
53-104 2.9 3.1 3.3 3.0
Resulted in average daily doses of approximately 40, 80, and 160 mg/kg per day to male mice and 30, 60, and 120 mg/kg per day to female mice.
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Thyroid Gland: The incidence of minimal follicular cell hypertrophy was significantly increased in 2,000 mg/L female mice when compared to the control group (0 mg/L, 3/48, severity grade 1.3; 500 mg/L, 2/50, severity grade 2.0; 1,000 mg/L, 5/49, severity grade 1.0; 2,000 mg/L, 14/50, severity grade 1.4). Histologically, affected follicles appeared small and were lined by slightly enlarged epithelial cells. The lumens of these follicles contained sparse amounts of generally pale colloid.
The incidence of thyroid gland cystic degeneration was significantly increased in 1,000 mg/L females when compared to the control group (25/48, 28/50, 34/49, 32/50). Microscopically, there were variations in follicle size, often with coalescence of contiguous, large follicles to form multilocular cysts. These cysts were usually lined by flattened epithelial cells, separated by variable amounts of connective tissue, and filled with pale colloid. Thyroid gland cystic degeneration was considered an aging change and not related to sodium chlorate administration.

Bone Marrow: The incidences of bone marrow hyperplasia were significantly increased in all exposed groups of female mice when compared to the control group (14/50, 28/50, 29/50, 31/50). The severity of this lesion in exposed females was slightly greater than in the controls (2.4, 2.6, 2.9, 2.7). Microscopically, bone marrow hyperplasia was characterized by an increase of hematopoietic cells in the marrow cavity. As in the rat, the increases in incidence and severity suggest a treatment-related effect.

Ovary: The incidence of granulosa cell hyperplasia of the ovary was significantly increased in 2,000 mg/L female mice when compared to the control group (0/45, 0/45, 3/47, 7/50). Microscopically, granulosa cell hyperplasia was characterized by one or more foci or a diffuse increase in the number of granulosa or luteal cells as pure or mixed populations. It was often difficult to discern focal hyperplastic changes from enlarged copora lutea. In general, these were not considered to be preneoplastic lesions.
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Pancreatic Islets:
There was a positive trend in the incidences of pancreatic islet cell adenoma or carcinoma (combined) in female mice that was composed primarily of adenomas (three of four neoplasms in the 2,000 mg/L group). The incidences of pancreatic islet adenoma and adenoma or carcinoma (combined) in 2,000 mg/L females exceeded the historical ranges for drinking water controls. The incidences of hyperplasia decreased with increasing exposure concentration.
Histologically, islet cell adenomas were characterized by enlarged islets composed of focal accumulations of well-differentiated islet cells with variable stromal components that compressed the adjacent parenchyma. On occasion, normal acinar cells were entrapped within the tumor. Because size is often considered an important criterion for discerning adenomas of endocrine organs, including the islets, it was noted that adenomas diagnosed in this study were significantly larger than those considered to be hyperplastic. In general, the hyperplastic lesions were smaller, affected multiple islets, and did not compress surrounding acinar tissue.
See table 1. "Overall remarks...."

Liver: The incidences of hepatocellular carcinoma were significantly greater in 500 and 1,000 mg/L females than in the control group (0 mg/L, 3/49; 500 mg/L, 13/50; 1,000 mg/L, 15/49; 2,000 mg/L, 9/50). Although not statistically significant, the incidence in 2,000 mg/L females was also increased. The incidences in all exposed groups of females exceeded the historical range for drinking water controls [12/149 (8%), range 4% to 14%]. Microscopically, these neoplasms were not well demarcated, primarily trabecular in growth pattern, and characterized by cords of atypical hepatocytes. When incidences of hepatocellular adenoma (30/49, 19/50, 26/49, 23/50) and carcinoma were combined (31/49, 26/50, 31/49, 26/50), there was no chemical effect. Due to this fact and because the increases were not exposure concentration-related, these carcinomas were not considered to be induced by sodium chlorate.
Details on results:
HISTORICAL CONTROL DATA (if applicable)
For the observed effects a comparison was made with historical control data. The concurrent control group represents the most valid comparison to the treated groups and is the only control group analyzed statistically in NTP bioassays. However, historical control data are often helpful in interpreting potential treatment-related effects, particularly for uncommon or rare neoplasm types.
Relevance of carcinogenic effects / potential:
Administration of sodium chlorate did not produce any clinical findings of toxicity and had no significant effect on body weights of males or water consumption by mice of either sex. Male mice may have been able to tolerate slightly higher exposure concentrations. Target organs for sodium chlorate toxicity in the 2-year study included the pancreatic islets and thyroid gland in female mice. The thyroid gland was considered to be a target organ for sodium chlorate toxicity because of the increases in the incidences of follicular cell hypertrophy in 1,000 and 2,000 mg/L female mice; the incidence was significantly increased at 2,000 mg/L. There was no evidence of thyroid gland effects in male or female mice after 3 weeks of exposure.
Several arguments support an association of pancreatic islet neoplasms with sodium chlorate administration. Spontaneous pancreatic islet cell tumors are rare in the B6C3F1 mouse (Boorman and Sills, 1999). In the 2-year mouse study, there was a positive trend in the incidences of pancreatic islet cell adenoma or carcinoma (combined) in females. The incidences of adenoma and adenoma or carcinoma (combined) in the 2,000 mg/L group exceeded the NTP historical range for drinking water controls.
- However, the incidences of these lesions were not increased in male mice.
- Furthermore, the incidences of pancreatic islet hyperplasia were not increased significantly in exposed mice of either sex.
Based on these data, the pancreatic islet cell response in female mice was considered an equivocal finding. Only one other NTP study, 2,4- and 2,6-toluene diisocyanate (NTP, 1986), demonstrated clear or some evidence of carcinogenicity in female rats based on an increased incidence of pancreatic islet adenomas.
Dose descriptor:
LOAEL
Effect level:
30 mg/kg bw/day
Sex:
female
Basis for effect level:
other: bone marrow hyperplasia
Remarks on result:
other: Effect type: toxicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
160 mg/kg bw/day
Sex:
male
Basis for effect level:
other: No effects observed
Remarks on result:
other: Effect type: toxicity (migrated information)
Conclusions:
There was no evidence of carcinogenic activity of sodium chlorate in male B6C3F1 mice exposed to 500, 1,000, or 2,000 mg/L. There was equivocal evidence of carcinogenic activity of sodium chlorate in female B6C3F1 mice based on marginally increased incidences of pancreatic islet neoplasms.
Executive summary:

Under GLP and according to methods equivalent to internationally accepted guidelines groups of 50 male and 50 female mice were exposed to drinking water containing 0, 500, 1,000, or 2,000 mg/L sodium chlorate for 2 years (equivalent to average daily doses of approximately 40, 80, and 160 mg/kg per day for male mice and 30, 60, and 120 mg/kg per day for female mice).

Survival of exposed mice was similar to that of the control groups. Mean body weights of exposed females were generally less than those of the control groups after week 84 of the study. Water consumption by exposed mice was generally similar to that by controls throughout the study. There was a positive trend in the incidences of pancreatic islet cell adenoma or carcinoma (combined) in female mice. Thyroid gland follicular cell hypertrophy was significantly increased in 2,000 mg/L females. The incidences of bone marrow hyperplasia were significantly increased in all exposed groups of females.

There was no evidence of carcinogenic activity of sodium chlorate in male B6C3F1 mice exposed to 500, 1,000, or 2,000 mg/L. There was equivocal evidence of carcinogenic activity of sodium chlorate in female B6C3F1 mice based on marginally increased incidences of pancreatic islet neoplasms. Based on these effects the LOAEL in female mice is 30 mg/kg bw day and the NOAEL in male mice is 160 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
5 mg/kg bw/day
Species:
rat

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on results of a 2 -year carcinogenicty study in rats and mice and information on the MoA, the sodium chlorate is not classified.

Additional information

The 2-year chronic NTP studies in mice and rats indicated thyroid effects in rats. There seemed to be a concentration-related increase in percentage of smaller follicles, often showing colloid depletion, which was visible from 5 mg/kg bw/day in males and females.


Although no haematological effects were observed in the chronic NTP study, in particular methaemoglobin forming, the incidence of bone marrow hyperplasia was possibly increased in the male rats and female mice (but lowered in male mice).


 


In the NTP carcinogenicity study, sodium chlorate resulted in a positive trend in the incidences of pancreatic islet cell adenoma or carcinoma (combined), in female mice although the authors considered these results in mice to be equivocal. The effect was only observed in only one sex, the incidences for either adenomas or adenomas and carcinomas (combined) were not statistically significant [the global incidence of hyperplasia plus adenomas remains flat over dose (9/46; 8/47; 6/49; 6/49).] Similar effects were not observed in the rat carcinogenicity study.


 


An increase of thyroid neoplasia in male rats (at 75 mg/kg bw/day) was seen. Taking into account the mechanism of action, which is a mechanism that does not directly act on the thyroid but acts via hormone imbalance, strongly suggested from the available data, sodium chlorate should not be considered as a potential human carcinogen. For further details on MoA see Annex I of the CSR: position paper Ledirac and Pontal 2008.


 


In rodents there is convincing evidence that thyroid hormone imbalance alone leads to tumour formation. Studies have been performed based on the effect of iodine deficiency, partial thyroidectomy and transplantation of TSH-secreting tumours. The weight of the evidence suggests that rodents are more sensitive than human subjects to thyroid tumour induction due to hormonal imbalances that cause elevated TSH levels. It is known for at least 20 different compounds to cause follicular cell neoplasms of the thyroid in rodents, however, none of these compounds is unequivocally associated with thyroid cancer in humans (Capen, 1999 and 2005).