Registration Dossier

Administrative data

Description of key information

Read-across data from sodium chlorate to assess the repeated dose toxicity of potassium chlorate is justified, because the toxicity is expected to be related to the chlorate ion and not to the sodium or potassium ion.


 


No data available for potassium chlorate. Cross reading to valid animal studies with sodium chlorate indicate that the overall lowest sub-chronic NOAEL is 100 mg sodium chlorate/kg bw/day, based on effects on erythrocytes. On a molecular weight basis this would be 115 mg potassium chlorate/kg bw/day.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March 1987 - July 1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study performed according to standard US EPA protocol and under GLP.
Qualifier:
according to guideline
Guideline:
EPA OPP 82-1 (90-Day Oral Toxicity)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
-Haematology, clinical biochemistry and histopathology only in 10 animals/sex/group. Humidity 23 - 86% in stead of 30 - 70%.
Principles of method if other than guideline:
- Haematology, clinical biochemistry and histopathology only in 10 animals/sex/group
- humidity 23 - 86% in stead of 30 - 70%
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., New York, USA
- Age at study initiation: 42 days old
- Weight at study initiation: males: mean 205 g, range 181-229 g; females: mean 143 g, range 129-168 g
- Fasting period before study: no info
- Housing: animals were doubly housed in elevated stainless steel wire mesh cages during the first week of the acclimatisation period and individually housed thereafter
- Diet (e.g. ad libitum): standard laboratory diet (Purina Certified Rodent Chow), ad lib
- Water (e.g. ad libitum): Elizabethtown Water Company, ad lib
- Acclimation period: 14 days (March 24 - April 6, 1987)


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 23 - 86
- Air changes (per hr): no info
- Photoperiod (hrs dark / hrs light): 12 h light/dark cycle (7 AM to 7 PM)


IN-LIFE DATES: From: April 7, 1987 (Pretest: March 31, 1987) To: July 6, 1987
Route of administration:
oral: gavage
Vehicle:
other: distilled water
Duration of treatment / exposure:
90 or 91 days depending on day of necropsy
(13 weeks)
Frequency of treatment:
daily (7/7)
Remarks:
Doses / Concentrations:
10 - 100 - 1000 mg/kg bw d
Basis:
actual ingested
No. of animals per sex per dose:
120 (60 males 60 females): 15 animals per sex per group (3 dose groups and 1 control group)
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: No
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily; once in the morning and once in the afternoon


BODY WEIGHT: Yes
- Time schedule for examinations: twice pretest, weekly during treatment and terminally (after fasting)


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): not applicable (however, food intake is examined weekly, beginning one week prior to treatment)


FOOD EFFICIENCY: not applicable


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): not applicable


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretest and termination


HAEMATOLOGY: Yes
- Time schedule for collection of blood: termination (week 13)


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: termination (week 13)


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
- Macroscopic: complete post mortem examinations were performed on all animals. External surface, all orifices, the cranial cavity, carcass, the external of the brain and spinal cord, nasal cavity and paranasal sinuses, the thoracic, abdominal and pelvic cavities and their viscera and cervical tissues and organs were examined.
- Microscopic: complete post mortem examinations were performed on all animals. Sectioned surfaces of the brain and spinal cord, nasal cavity and paranasal sinuses, the thoracic, abdominal and pelvic cavities and their viscera and cervical tissues and organs were examined.
Statistics:
Body weight, food consumption, hematology and clinical chemistry parameters, organs weights and organ/body weights ratios were analyzed. Mean values of all dose groups were compared to the control at each time interval. Statistical evaluation of equality of means was made by the appropriate one way analysis of variance technique, followed by a multiple comparison procedure if needed. First, Bartlett's test was performed to determine if groups had equal variance. If the variances were equal, parametric procedures were used; if not, nonparametric procedures were used. The parametric procedures were the standard one way ANOVA using the F distribution to assess significance. If significant differences among the means were indicated, Dunnett's test was used to determine which means were significantly different from the control. If a nonparametric procedure for testing equality of means was needed, the Kruskal-Wallis test was used, and if differences were indicated a summed rank test (Dunn) was used to determine which treatments differed from control. A statistical test for trend in the dose levels was also performed. In the parametric case (i .e., equal variance) standard regression techniques with a test for trend and lack of fit were used. In the nonparametric case Jonckheere's test for monotonic trend was used. The test for equal variance (Bartlett's) was conducted at the 1%, two-sided risk level. All other statistical tests were conducted at the 5% and I%, two-sided risk level.
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):
effects observed, treatment-related
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
Mortality:
- Time of death: day 69 and day 30
- Number of deaths at each dose: one 100 mg/kg bw d male and one 1000 mg/kg d female. No abnormaltities were found. (due to the lack of significant physical observations and histopathological lesions these deaths are not considered to be related to sodium chlorate administration).
Clinical signs: no sodium chlorate related clinical signs were observed.


BODY WEIGHT AND WEIGHT GAIN
Body weight gain: All animals gained weight during the study. The body weights for the males did not differ from the control group body weights. Mean group body weights for 10 and 1000 mg/kg bw d females were significantly lower than for the control animals. From historical data it was shown that the body weight gain of the control animals was higher than expected. Also no dose related effect could be found. Therefore it is suggested that the observed effect is due to normal physiological variation and not related to sodium chlorate administration.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) / WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Food/water consumption: : Some increase of food consumption was seen (male 10 and 100 mg/kg bw/d week 6 and 7, male and female 100 mg/kg bw/d week 10) This effect was not sodium chlorate related.


OPHTHALMOSCOPIC EXAMINATION
Ophthalmoscopic examination: no sodium chlorate related ocular abnormalities were observed.


HAEMATOLOGY
Haematology: The 1000 mg/kg d animals showed a statistically significant lower mean erythrocyte count,
hemoglobin concentration and percent hematocrit as compared with the controls. Mean Cortpuscular Hemoglobin (MCH), Mean Corpuscular Volume (MCV), and Mean Corpuscular Hemoglobin Concentration (MCHC) as well as reticulocyte counts and percent haemoglobin for high-dose animals were comparable to control values. Females were more effected than males. These findings are consistent with a normocytic, non regenerative anemia and were considered related to sodium chlorate administration.

Mean values for each dose group per sex for every parameter measured are shown below (significant figures = *).

1 METHGB methemoglobin percent
2 HGB hemoglobin concentration g/dl
3 HCT Hematocrit percent
4 RBC erythrocyte count 10e6/microliter
5 PLAT platelet count 10e5/microliter
6 MCV mean corpuscular volume cubic u
7 MCH Mean Cortpuscular Hemoglobin uu g
8 MCHC Mean Corpuscular Hemoglobin Concentration g/dl
9 WBC Total leukocyte count 10e3/microliter
10 RETIC reticulocyte count % RBC

Males mg/kg bw
1 2 3 4 5 6 7 8 9 10
0 0.6 15.2 43 7.17 16.41 60 21.2 35.1 17.3 0
10 0.5 15.2 43 7.24 15.80 60 21.0 35.4 16.9 -
100 0.7 15.2 43 7.23 15.81 60 21.0 35.4 14.3 -
1000 0.5 14.6 41* 6.75 16.76 60 21.7 35.9 14.5 0

Females mg/kg bw
1 2 3 4 5 6 7 8 9 10
0 0.6 14.9 43 6.62 16.35 65 22.6 34.5 9.6 0
10 0.7 15.3 44 6.78 16.08 64 22.6 35.0 9.3 -
100 0.5 14.8 43 6.63 15.97 64 22.3 34.8 7.2 -
1000 0.6 13.9* 39* 6.24* 18.45 63 22.3 35.3 9.7 0.1


CLINICAL CHEMISTRY
Clinical chemistry: no sodium chlorate related abnormalities were observed.


ORGAN WEIGHTS
Organ weights: 1000 mg/kg d males and females showed a significant slight decrease in absolute adrenal weights compared to the controls. Also in the 1000 mg/kg bw males a trend was seen towards a decrease in the adrenal to body weight ratio. Other effects were not attributed to sodium chlorate exposure. See Table 1.


GROSS PATHOLOGY
Gross pathology: no sodium chlorate related effects were observed.
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no significant effects observed
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
haematology
mortality
organ weights and organ / body weight ratios
Critical effects observed:
not specified

Table 1. Absolute and relative adrenal weight

 

Dose-level (mg/kg/day)

0

10

100

1000

Sex

M

F

M

F

M

F

M

F

Body weight (g)

519.0

308.5

548.4

278.0**

514.8

293.8

494.3

276.6**

Absolute adrenal weight (g)

0.0623

0.0655

0.0554

0.0620

0.0636

0.0702

0.0487*

0.0526*

Relative adrenal weight (g/g body weightх10000)

1.21

2.13

1.02

2.24

1.22

2.38

0.99

1.90

Conclusions:
Oral administration of Sodium Chlorate for 90 days resulted in no toxicologically significant effects at dose levels of 10 and 100 mg/kg bw/day. The NOAEL was 100 mg/kg bw/day and the LOAEL was 1000 mg/kg bw/day.
Executive summary:

The study was designed to investigate the systemic toxicity of the test material and complies the recommendations of the OECD Guidelines for Testing of Chemicals No. 408.


 


The test material was administered by gavage to three groups, each consisting of 15 male and 15 female Sprague-Dawley CD strain rats, for ninety consecutive days, at dose levels of 10, 100 and 1000 mg/kg/day. A control group of 15 males and 15 females was dosed with vehicle alone (distilled water). Clinical signs, bodyweight and food consumption were monitored during the study. Haematology and clinical chemistry were evaluated for 10 animals/sex/group at the end of the study. Ophthalmoscopic examination was also performed. All animals were subjected to a gross necropsy examination and a comprehensive histopathological evaluation of tissues from test and control groups was performed on 10 animals/sex/group. In addition, the lungs, liver, kidneys and spleen of 10 animals/sex/group from the low-dose and mid-dose group were examined microscopically.


 


One mid-dose male died on Day 69 and one high-dose female died on Day 30. These deaths were not considered due to the administration of sodium chlorate. Although mean group body weights for low- and high-dose females were statistically significantly lower than for control animals throughout most of the study, the absence of a similar finding in the mid-dose females and treated males coupled with historical control data which indicated control females gained more weight than normally expected suggests the lower body weights noted were not attributable to test material administration.


 


Abnormalities in haematology parameters related to administration of sodium chlorate were limited to a decrease in erythrocyte count, hemoglobin concentration, and percent hematocrit for high-dose animals, findings consistent with anemia. Examination of terminal organ and body weights and organ to body weight ratios revealed a number of statistically significant differences between control and treated groups.


 


However, with the exception of a slight decrease (p 0.05) in adrenal weight for high-dose animals when compared to controls, statistical differences noted were considered a result of differences in mean group body weights for low- and mid-dose females and not related to sodium chlorate administration.


It is noteworthy that in 1000 mg/kg/day males, only 2/15 absolute, 0/15 relative-to-brain and 3/15 relative-to-body weight values were lower than the lowest concurrent control value. In 1000 mg/kg/day females, only 2/14 absolute, 4/14 relative-to-brain, and 3/14 relative-to-body weights were lower than the lowest concurrent control value. No correlating gross observations (e.g. small, reduced in size) were recorded in adrenal glands.


There was no good correlation between the histopathological observation of vacuoles and the decreased adrenal weights observed in this study. Males had slightly greater decreases in adrenal weights than did females, but vacuoles were observed more frequently in females than in males. These histopathological findings were considered by the study pathologist to be not related to the administration of sodium chlorate.


In addition, no indication of decreased adrenal weights was mentioned in the carcinogenicity studies in both rats and mice, and no statistically significant adrenal weight changes were reported between treated groups (up to 500 mg/kg/day) and controls in the two-generation study, in both male and female rats.


 


Evaluation of physical observations, food consumption, ophthalmology, clinical chemistry values, and gross and microscopic pathology revealed no evidence of an effect of test material administration.


 


Oral administration of the test material, Sodium Chlorate, to rats for a period of ninety consecutive days at dose levels of up to 1000 mg/kg/day resulted in no toxicologically significant effects at dose levels of 10 and 100 mg/kg/day. The “No Observed Adverse Effect Level" (NOAEL) is considered to be 100 mg/kg/day and the “Lowest Observed Adverse Effect Level” (LOAEL) is considered to be 1000 mg/kg/day.

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
See the RAAF document.
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
read-across source
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
See 'Details on results'
Mortality:
mortality observed, non-treatment-related
Description (incidence):
See 'Details on results'
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
See 'Details on results'
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
See 'Details on results'
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, non-treatment-related
Description (incidence and severity):
See 'Details on results'
Ophthalmological findings:
no effects observed
Description (incidence and severity):
See 'Details on results'
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Normocytic, non regenerative anemia
See 'Details on results'
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
See 'Details on results'
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
See 'Details on results'
Gross pathological findings:
no effects observed
Description (incidence and severity):
See 'Details on results'
Details on results:
CLINICAL SIGNS AND MORTALITY
Mortality:
- Time of death: day 69 and day 30
- Number of deaths at each dose: one 100 mg/kg bw d male and one 1000 mg/kg d female. No abnormaltities were found. (due to the lack of significant physical observations and histopathological lesions these deaths are not considered to be related to sodium chlorate administration).
Clinical signs: no sodium chlorate related clinical signs were observed

BODY WEIGHT AND WEIGHT GAIN
Body weight gain: All animals gained weight during the study. The body weights for the males did not differ from the control group body weights. Mean group body weights for 10 and 1000 mg/kg bw d females were significantly lower than for the control animals. From historical data it was shown that the body weight gain of the control animals was higher than expected. Also no dose related effect could be found. Therefore it is suggested that the observed effect is due to normal physiological variation and not related to sodium chlorate administration.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) / WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Food/water consumption: : Some increase of food consumption was seen (male 10 and 100 mg/kg bw/d week 6 and 7, male and female 100 mg/kg bw/d week 10) This effect was not sodium chlorate related.

OPHTHALMOSCOPIC EXAMINATION
Ophthalmoscopic examination: no sodium chlorate related ocular abnormalities were observed

HAEMATOLOGY
Haematology: The 1000 mg/kg d animals showed a statistically significant lower mean erythrocyte count, hemoglobin concentration and percent hematocrit as compared with the controls. Mean Cortpuscular Hemoglobin (MCH), Mean Corpuscular Volume (MCV), and Mean Corpuscular Hemoglobin Concentration (MCHC) as well as reticulocyte counts and percent haemoglobin for high-dose animals were comparable to control values. Females were more effected than males. These findings are consistent with a normocytic, non regenerative anemia and were considered related to sodium chlorate administration.

Mean values for each dose group per sex for every parameter measured are shown below (significant figures = *).

1 METHGB methemoglobin percent
2 HGB hemoglobin concentration g/dl
3 HCT Hematocrit percent
4 RBC erythrocyte count 10e6/microliter
5 PLAT platelet count 10e5/microliter
6 MCV mean corpuscular volume cubic u
7 MCH Mean Cortpuscular Hemoglobin uu g
8 MCHC Mean Corpuscular Hemoglobin Concentration g/dl
9 WBC Total leukocyte count 10e3/microliter
10 RETIC reticulocyte count % RBC

Males mg/kg bw
1 2 3 4 5 6 7 8 9 10
0 0.6 15.2 43 7.17 16.41 60 21.2 35.1 17.3 0
10 0.5 15.2 43 7.24 15.80 60 21.0 35.4 16.9 -
100 0.7 15.2 43 7.23 15.81 60 21.0 35.4 14.3 -
1000 0.5 14.6 41* 6.75 16.76 60 21.7 35.9 14.5 0

Females mg/kg bw
1 2 3 4 5 6 7 8 9 10
0 0.6 14.9 43 6.62 16.35 65 22.6 34.5 9.6 0
10 0.7 15.3 44 6.78 16.08 64 22.6 35.0 9.3 -
100 0.5 14.8 43 6.63 15.97 64 22.3 34.8 7.2 -
1000 0.6 13.9* 39* 6.24* 18.45 63 22.3 35.3 9.7 0.1


CLINICAL CHEMISTRY
Clinical chemistry: no sodium chlorate related abnormalities were observed

ORGAN WEIGHTS
Organ weights: 1000 mg/kg d males and females showed a significant slight decrease in absolute adrenal weights compared to the controls. Also in the 1000 mg/kg bw males a trend was seen towards a decrease in the adrenal to body weight ratio. Other effects were not attributed to sodium chlorate exposure. See Table 1.

GROSS PATHOLOGY
Gross pathology: no sodium chlorate related effects were observed
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology
Critical effects observed:
not specified

Table 1. Absolute and relative adrenal weight

 

Dose-level (mg/kg/day)

0

10

100

1000

Sex

M

F

M

F

M

F

M

F

Body weight (g)

519.0

308.5

548.4

278.0**

514.8

293.8

494.3

276.6**

Absolute adrenal weight (g)

0.0623

0.0655

0.0554

0.0620

0.0636

0.0702

0.0487*

0.0526*

Relative adrenal weight (g/g body weightх10000)

1.21

2.13

1.02

2.24

1.22

2.38

0.99

1.90

Conclusions:
Oral administration of Sodium Chlorate for 90 days resulted in no toxicologically significant effects at dose levels of 10 and 100 mg/kg bw/day. The NOAEL was 100 mg/kg bw/day and the LOAEL was 1000 mg/kg bw/day.
Executive summary:

The study was designed to investigate the systemic toxicity of the test material and complies the recommendations of the OECD Guidelines for Testing of Chemicals No. 408.


 


The test material was administered by gavage to three groups, each consisting of 15 male and 15 female Sprague-Dawley CD strain rats, for ninety consecutive days, at dose levels of 10, 100 and 1000 mg/kg/day. A control group of 15 males and 15 females was dosed with vehicle alone (distilled water). Clinical signs, bodyweight and food consumption were monitored during the study. Haematology and clinical chemistry were evaluated for 10 animals/sex/group at the end of the study. Ophthalmoscopic examination was also performed. All animals were subjected to a gross necropsy examination and a comprehensive histopathological evaluation of tissues from test and control groups was performed on 10 animals/sex/group. In addition, the lungs, liver, kidneys and spleen of 10 animals/sex/group from the low-dose and mid-dose group were examined microscopically.


 


One mid-dose male died on Day 69 and one high-dose female died on Day 30. These deaths were not considered due to the administration of sodium chlorate. Although mean group body weights for low- and high-dose females were statistically significantly lower than for control animals throughout most of the study, the absence of a similar finding in the mid-dose females and treated males coupled with historical control data which indicated control females gained more weight than normally expected suggests the lower body weights noted were not attributable to test material administration.


 


Abnormalities in haematology parameters related to administration of sodium chlorate were limited to a decrease in erythrocyte count, hemoglobin concentration, and percent hematocrit for high-dose animals, findings consistent with anemia. Examination of terminal organ and body weights and organ to body weight ratios revealed a number of statistically significant differences between control and treated groups.


 


However, with the exception of a slight decrease (p 0.05) in adrenal weight for high-dose animals when compared to controls, statistical differences noted were considered a result of differences in mean group body weights for low- and mid-dose females and not related to sodium chlorate administration.


It is noteworthy that in 1000 mg/kg/day males, only 2/15 absolute, 0/15 relative-to-brain and 3/15 relative-to-body weight values were lower than the lowest concurrent control value. In 1000 mg/kg/day females, only 2/14 absolute, 4/14 relative-to-brain, and 3/14 relative-to-body weights were lower than the lowest concurrent control value. No correlating gross observations (e.g. small, reduced in size) were recorded in adrenal glands.


There was no good correlation between the histopathological observation of vacuoles and the decreased adrenal weights observed in this study. Males had slightly greater decreases in adrenal weights than did females, but vacuoles were observed more frequently in females than in males. These histopathological findings were considered by the study pathologist to be not related to the administration of sodium chlorate.


In addition, no indication of decreased adrenal weights was mentioned in the carcinogenicity studies in both rats and mice, and no statistically significant adrenal weight changes were reported between treated groups (up to 500 mg/kg/day) and controls in the two-generation study, in both male and female rats.


 


Evaluation of physical observations, food consumption, ophthalmology, clinical chemistry values, and gross and microscopic pathology revealed no evidence of an effect of test material administration.


 


Oral administration of the test material, Sodium Chlorate, to rats for a period of ninety consecutive days at dose levels of up to 1000 mg/kg/day resulted in no toxicologically significant effects at dose levels of 10 and 100 mg/kg/day. The “No Observed Adverse Effect Level" (NOAEL) is considered to be 100 mg/kg/day and the “Lowest Observed Adverse Effect Level” (LOAEL) is considered to be 1000 mg/kg/day.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
February 1987 - May 1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study performed according to standard US EPA protocol and under GLP.
Qualifier:
according to guideline
Guideline:
EPA OPP 82-1 (90-Day Oral Toxicity)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)
GLP compliance:
yes
Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Marshall Farms U.S.A., Inc. New York, USA
- Age at study initiation: 5.5 - 6.5 months
- Weight at study initiation: 8.1 kg (range 6.8 - 9.6) males, 7.8 kg (range 6.2 - 8.9) females
- Housing: Individually
- Diet (e.g. ad libitum): Standard laboratory diet (Purina Certtified Canine Diet), presented fresh daily for 4.5 hours
- Water (e.g. ad libitum): ad lib
- Acclimation period: 4 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 28
- Photoperiod (hrs dark / hrs light): 12 hour light/dark


IN-LIFE DATES: From: February 13, 1987 To: May 21, 1987
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Appropriate amounts of the test substance were suspended in the vehicle weekly to yield dose levels of 10, 60 and 360 mg/kg/day at a constant dose volume of 1 ml/kg/dose. Individual doses were adjusted by most recent weekly body weight. Control animals were administered the vehicle (distilled water) at the same dose volume.

VEHICLE
- Justification for use and choice of vehicle (if other than water): distilled water
- Concentration in vehicle: 10, 60 and 360 mg/ml
- Amount of vehicle (if gavage): 1 ml/kg/dose
- Lot/batch no. (if required): -
- Purity: -
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Ten milliliter aliquots of dosing solution were taken for the control group and each dose level for Weeks 1, 4, 8 and 12 and analyses for concentration were performed by the Department of Metabolism and Analytical Chemistry.
Duration of treatment / exposure:
90-93 days, depending on the day of necropsy
Frequency of treatment:
daily (7 days per week) through the day prior to necropsy
Remarks:
Doses / Concentrations:
10 - 60 - 360 mg/kg/d
Basis:
actual ingested
No. of animals per sex per dose:
4 animals/sex/dose (16 males, 16 females)
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: No
Positive control:
No.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: pretest and weekly thereafter


BODY WEIGHT: Yes
- Time schedule for examinations: pretest and weekly thereafter and terminally (after fasting)


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption: pretest and weekly thereafter (measured and recorded daily 7/7)


FOOD EFFICIENCY: No


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretest and termination


HAEMATOLOGY: Yes
- Time schedule for collection of blood: pretest, week 6, week 13
- Parameters examined: methemoglobin, hemoglobin, hematocrit, erythrocyte count and morphology, platelet, reticulocyte, total and differential leukocyte


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: pretest, week 6, week 13
- Parameters examined: serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, blood urea nitrogen, creatinine, glucose, total protein, albumin, bilirubin, sodium, potassium, chloride, calciam, inorganic phosphorus


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No


OTHER: Organ weights
Sacrifice and pathology:
- Macroscopic: complete post mortem examinations were performed on all animals. External surface, all orifices, the cranial cavity, carcass, the external of the brain and spinal cord, nasal cavity and paranasal sinuses, the thoracic, abdominal and pelvic cavities and their viscera and cervical tissues and organs were examined.
- Microscopic: complete post mortem examinations were performed on all animals. Sectioned surfaces of the brain and spinal cord, nasal cavity and paranasal sinuses, the thoracic, abdominal and pelvic cavities and their viscera and cervical tissues and organs were examined.
Statistics:
Body weight, food consumption, hematology and clinical chemistry parameters, terminal organ and body weights weights and organ/body weights ratios were analyzed. Mean values of all dose groups were compared to the control at each time interval. Statistical evaluation of equality of means was made by the appropriate one way analysis of variance technique, followed by a multiple comparison procedure if needed. First, Bartlett's test was performed to determine if groups had equal variance. If the variances were equal, parametric procedures were used; if not, nonparametric procedures were used. The parametric procedures were the standard one way ANOVA using the F distribution to assess significance. If significant differences among the means were indicated, Dunnett's test was used to determine which means were significantly different from the control. If a nonparametric procedure for testing equality of means was needed, the Kruskal-Wallis test was used, and if differences were indicated a summed rank test (Dunn) was used to determine which treatments differed from control. A statistical test for trend in the dose levels was also performed. In the parametric case (i .e., equal variance) standard regression techniques with a test for trend and lack of fit were used. In the nonparametric case Jonckheere's test for monotonic trend was used. The test for equal variance (Bartlett's) was conducted at the 1%, two-sided risk level. All other statistical tests were conducted at the 5% and I%, two-sided risk level.
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):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
- Mortality and time to death: all animals survived until study termination
- Clinical signs: One 360 mg/kg bw female showed statistically significant emesis during the first 3 weeks of the study. Other clinical signs seen were not related to sodium chlorate treatment.

BODY WEIGHT AND WEIGHT GAIN
- Body weight gain: One male 360 mg/kg bw animal lost 1 kg during week 11 together with a decrease in food consumption. All other animals gained weight during the study and no sodium chlorate related effect on body weight was seen.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- Food/water consumption: No differences were seen between the exposed and the control group.

FOOD EFFICIENCY
-

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
-

OPHTHALMOSCOPIC EXAMINATION
-

HAEMATOLOGY
- Haematology: 360 mg/kg bw animals showed a slightly elevated mean percent methemoglobin at study termination. This effect was due to samples from 2 animals (4002 and 4502), second samples from a redraw did not show this effect. Therefore it is not likely that the seen effect is induced by sodium chlorate exposure.

Mean methemoglobin in %
mg/kg d 0 10 60 360
Pretest
Males 0.7 0.5 0.7 0.5
Females 0.6 1.0 1.2 0.9
6 weeks
Males 0.4 0.5 0.7 0.6
Females 0.4 0.6 0.8 0.8
13 weeks
Males 0.5 0.4 0.4 0.9
Females 0.4 0.4 0.7 0.9
13 weeks redraw
Males 0.5 0.4 0.4 0.6
Females 0.5 0.5 0.8 0.4

Individual data affected animals:
360 mg/kg d pretest 6 weeks 13 weeks redraw 13 weeks
Male (4002) 0.7 0.8 2.1 1.0
Female (4502) 1.7 1.7 2.5 0.6


CLINICAL CHEMISTRY
Although a few statistically significant differences between control and treated groups were seen (an elevated sodium value for mid-dose females and an elevated potassium value for high-dose females at study termination), these differences were slight and not considered related to sodium chlorate administration. Also noted at study termination were low blood urea nitrogen values for several animals in the high-dose group. A low value for this parameter is not clinically significant nor was it considered suggestive of a treatment-related effect.

URINALYSIS
-

NEUROBEHAVIOUR
-

ORGAN WEIGHTS
- Organ weights: An significant but slight increase in testes/epididymes to body weight ratio was seen in the 60 mg/kg bw animals. Also a trend towards increase in mean group spleen weight was seen for males. These effects were not related to treatment.

GROSS PATHOLOGY
- Gross pathology: No treatment related effects were seen.

HISTOPATHOLOGY: NON-NEOPLASTIC
Abnormal microscopic findings were primarily encountered in the lungs, liver and kidneys. The changes observed were deemed to be spontaneous with similar incidence between control and treated groups. Changes in other tissues were few and were sporadic in occurrence. No microscopic finding was considered to be indicative of a treatment-related effect.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
-

HISTORICAL CONTROL DATA (if applicable)
-
Dose descriptor:
NOAEL
Effect level:
360 mg/kg bw/day (nominal)
Sex:
male/female
Critical effects observed:
not specified
Conclusions:
Oral administration of Sodium Chlorate in dogs for 90 days dose levels of 10, 60 and 360 mg/kg/day did not induce any significant observable alterations or abnormalities when compared to controls. The NOAEL was 360 mg/kg bw.
Executive summary:

The study was designed to investigate the systemic toxicity of Sodium Chlorate and complies the recommendations of the OECD Guidelines for Testing of Chemicals No. 409.The test substance was administered daily (1 h/day, 7 days/week) for a period of 3 months as gavage to Beagle dogs. One control group (vehicle) and three treated groups were tested, each consisting of 4 males and 4 females. Dose levels were 10, 60 and 360 mg/kg/day. The following parameters were evaluated: clinical signs; ophthalmoscopic examination; body weight and food consumption; haematology and clinical chemistry; pathology and macroscopy at termination; organ weights and histopathology.


All animals survived throughout the study. Adverse clinical signs related to sodium chlorate administration were limited to emesis in one high-dose female during the first three weeks of the study. Although one high-dose male exhibited a one kilogram weight loss during Week 11, which was paralleled by a decrease in food consumption, in general, body weight gains between control and treated groups were comparable. Evaluation of food consumption, clinical laboratory studies, ophthalmoscopic examinations, organ weights and organ to body weight ratios, and gross and microscopic pathology revealed no evidence of an effect of sodium chlorate administration.


Oral administration of Sodium Chlorate in dogs for 90 days dose levels of 10, 60 and 360 mg/kg/day did not induce any significant observable alterations or abnormalities when compared to controls. The NOAEL was 360 mg/kg bw.

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
See the RAAF document.
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
read-across source
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
See 'Details on results'
Mortality:
no mortality observed
Description (incidence):
See 'Details on results'
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
See 'Details on results'
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
See 'Details on results'
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
See 'Details on results'
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
See 'Details on results'
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
See 'Details on results'
Gross pathological findings:
no effects observed
Description (incidence and severity):
See 'Details on results'
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
See 'Details on results'
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
See 'Details on results'
Details on results:
CLINICAL SIGNS AND MORTALITY
- Mortality and time to death: all animals survived until study termination
- Clinical signs: One 360 mg/kg bw female showed statistically significant emesis during the first 3 weeks of the study. Other clinical signs seen were not related to sodium chlorate treatment.

BODY WEIGHT AND WEIGHT GAIN
- Body weight gain: One male 360 mg/kg bw animal lost 1 kg during week 11 together with a decrease in food consumption. All other animals gained weight during the study and no sodium chlorate related effect on body weight was seen.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- Food/water consumption: No differences were seen between the exposed and the control group.

FOOD EFFICIENCY
-

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
-

OPHTHALMOSCOPIC EXAMINATION
-

HAEMATOLOGY
- Haematology: 360 mg/kg bw animals showed a slightly elevated mean percent methemoglobin at study termination. This effect was due to samples from 2 animals (4002 and 4502), second samples from a redraw did not show this effect. Therefore it is not likely that the seen effect is induced by sodium chlorate exposure.

Mean methemoglobin in %
mg/kg d 0 10 60 360
Pretest
Males 0.7 0.5 0.7 0.5
Females 0.6 1.0 1.2 0.9
6 weeks
Males 0.4 0.5 0.7 0.6
Females 0.4 0.6 0.8 0.8
13 weeks
Males 0.5 0.4 0.4 0.9
Females 0.4 0.4 0.7 0.9
13 weeks redraw
Males 0.5 0.4 0.4 0.6
Females 0.5 0.5 0.8 0.4

Individual data affected animals:
360 mg/kg d pretest 6 weeks 13 weeks redraw 13 weeks
Male (4002) 0.7 0.8 2.1 1.0
Female (4502) 1.7 1.7 2.5 0.6


CLINICAL CHEMISTRY
Although a few statistically significant differences between control and treated groups were seen (an elevated sodium value for mid-dose females and an elevated potassium value for high-dose females at study termination), these differences were slight and not considered related to sodium chlorate administration. Also noted at study termination were low blood urea nitrogen values for several animals in the high-dose group. A low value for this parameter is not clinically significant nor was it considered suggestive of a treatment-related effect.

URINALYSIS
-

NEUROBEHAVIOUR
-

ORGAN WEIGHTS
- Organ weights: An significant but slight increase in testes/epididymes to body weight ratio was seen in the 60 mg/kg bw animals. Also a trend towards increase in mean group spleen weight was seen for males. These effects were not related to treatment.

GROSS PATHOLOGY
- Gross pathology: No treatment related effects were seen.

HISTOPATHOLOGY: NON-NEOPLASTIC
Abnormal microscopic findings were primarily encountered in the lungs, liver and kidneys. The changes observed were deemed to be spontaneous with similar incidence between control and treated groups. Changes in other tissues were few and were sporadic in occurrence. No microscopic finding was considered to be indicative of a treatment-related effect.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
-

HISTORICAL CONTROL DATA (if applicable)
-
Dose descriptor:
NOAEL
Effect level:
360 mg/kg bw/day (nominal)
Sex:
male/female
Critical effects observed:
not specified
Conclusions:
Oral administration of Sodium Chlorate in dogs for 90 days dose levels of 10, 60 and 360 mg/kg/day did not induce any significant observable alterations or abnormalities when compared to controls. The NOAEL was 360 mg/kg bw.
Executive summary:

The study was designed to investigate the systemic toxicity of Sodium Chlorate and complies the recommendations of the OECD Guidelines for Testing of Chemicals No. 409.The test substance was administered daily (1 h/day, 7 days/week) for a period of 3 months as gavage to Beagle dogs. One control group (vehicle) and three treated groups were tested, each consisting of 4 males and 4 females. Dose levels were 10, 60 and 360 mg/kg/day. The following parameters were evaluated: clinical signs; ophthalmoscopic examination; body weight and food consumption; haematology and clinical chemistry; pathology and macroscopy at termination; organ weights and histopathology.


All animals survived throughout the study. Adverse clinical signs related to sodium chlorate administration were limited to emesis in one high-dose female during the first three weeks of the study. Although one high-dose male exhibited a one kilogram weight loss during Week 11, which was paralleled by a decrease in food consumption, in general, body weight gains between control and treated groups were comparable. Evaluation of food consumption, clinical laboratory studies, ophthalmoscopic examinations, organ weights and organ to body weight ratios, and gross and microscopic pathology revealed no evidence of an effect of sodium chlorate administration.


Oral administration of Sodium Chlorate in dogs for 90 days dose levels of 10, 60 and 360 mg/kg/day did not induce any significant observable alterations or abnormalities when compared to controls. The NOAEL was 360 mg/kg bw.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Unknown
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study is not performed under GLP or according to standard protocol. It is not mentioned at what frequency animals are inspected for clinical signs or mortality. It is not mentioned where the sodium chlorate was obtained or any further information. One animal died and the time of death is not mentioned. No values and no statistical evaluation of the thyriod effect are presented in the publication, it is difficult to evaluate its relevance. In addition, the thyroid weight was not measured. No data on: number of animal, batch No. and purity unknown, some data missing, no individual data, confusion between sodium chlorate and chlorate. Therefore the study is only considered as supportive information.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Principles of method if other than guideline:
Method: other: no guidelines specified
Principles other than OECD Guideline:
- Study is not performed under GLP or according to standard protocol.
- 10 rats per group instead of 20 animals per group.
- It is not mentioned at what frequency animals are inspected for clinical signs or mortality.
- It is not mentioned where the sodium chlorate was obtained or any further information.
- One animal died and the time of death is not mentioned.
- No values and no statistical evaluation of the thyriod effect are presented in the publication, it is difficult to evaluate its relevance.
- The thyroid weight was not measured.
GLP compliance:
not specified
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles Rivers Laboratories (N. Wilmington, MA)
- Age at study initiation: 70 days of age
- Weight at study initiation: no data
- Fasting period before study: no info
- Housing: no info
- Diet (e.g. ad libitum): ad lib
- Water (e.g. ad libitum): ad lib
- Acclimation period: 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 24
- Humidity (%): 40 - 60
- Air changes (per hr): no info
- Photoperiod (hrs dark / hrs light): 12-hour/day/night cycle


IN-LIFE DATES: no info
Route of administration:
oral: drinking water
Vehicle:
other: distilled water; extra sodium was added to the low-dose and mid-dose group to reach a final concentration of sodium of 48mM.
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: no detailed information
the dosing groups were:
1. distilled water control
2. 48 mM saline control (sodium chloride)
3. 3.0 mM sodium chlorate
4. 12.0 mM sodium chlorate
5. 48.0 mM sodium chlorate
The final sodium concentration was 48.0 mM for each group except the distilled water control.


VEHICLE
- Justification for use and choice of vehicle (if other than water): sodium concentration was adjusted by adding sodium chloride when necessary.
Duration of treatment / exposure:
3 months; 90-day exposure period
Frequency of treatment:
daily 7/7
Remarks:
Doses / Concentrations:
3.0, 12.0, 48.0 mM (apprioximately 0.3, 1.3 and 5.1 g/L)
Basis:
nominal in water
No. of animals per sex per dose:
10/sex/group
Control animals:
no
Details on study design:
Post-exposure period: no
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No


DETAILED CLINICAL OBSERVATIONS: No detailed observations.


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): not applicable (however, recorded weekly)


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: every other day during exposure period


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: termination
- Anaesthetic used for blood collection: Yes, pentobarbital anesthesia (60 mg/kg)
- Animals fasted: Yes, for 18 hours prior to anesthesia
- How many animals: all
- Parameters checked in table [No.?] were examined: hemoglobin, hematocrit, mean corpuscular volume, red blood cell count, white blood cell count and reticulocyte count. leukocytes were further differentiated: neutrophils, eosinophils, basophils, lymphocytes, monocytes.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: termination
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table [No.?] were examined: alanine aminotransaminase, aspartate aminotransaminase, lactate dehydrogenase, creatinine, cholesterol, phosphoros, calcium, glucose, blood urea nitrogen.


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes: Macroscopic: the body and major organs (adrenal glands, gonads, heart, kidneys, lungs, liver, spleen, and thymus) were weighed.
HISTOPATHOLOGY: Yes: Microscopic: On half of the control and all of the high dose animals were examined. These tissues included: all gross lesions, duodenum, skin, jejunum, mandibular lymphnodes, mesenteric lymph nodes, tongue, salivary glands, trachea, thigh muscle, ileum, sciatic nerve, colon, rectum, stemum, femur or vertebrate/marrow, cecum, thymus, lungs and bronchi, liver, hart, aorta, pancreas, spleen, parathyroids, kidneys, esophagus, adrenals, stomach, urinary bladder, seminal vesicles, prostate, testes including epididymis, ovaries, uterus, nasal cavity, nasal turbinates, brain, preputial ot clitoral glands, and Zymbal's gland.
Other examinations:
No.
Statistics:
Analysis of variance were used to analyze each of the response measures when data was normally distributed. Because of the nature of some clinical measures a non parametrical analysis of variance procedure, the Kruskal- Wallis test was used to look for differences among those groups. Males and females were considered separately in all statistical analysis.
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):
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY
- Number of deaths at each dose: one animals in the distilled water control group died. Necropsy findings did not reveal the cause of death. Time of death: unknown.
- During the course of chlorate exposure, no behavioural or clinical abnormalities were noted.

BODY WEIGHT AND WEIGHT GAIN
- Body weight gain: The high dose group (both sexes) also showed a significantly lower final body weight when compared to controls.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) / WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Food/water consumption: No statistically significant differences were seen in food consumption. The water consumption significantly increased in the high dose group (both sexes) as well as in the low dose group (females) and saline control group (expressed as a percentage of body weight).
Actual dose received by dose level by sex: achieved doses were calculated to be: 0.36, 1.20, and 6.14 mM chlorate ion/kg d in males and 0.52, 1.96 and 9.6 mM chlorate ion/kg d in females (about 38, 128 and 653 mg sodium chlorate/kg d in males and 55, 209 and 1022 mg sodium chlorate/kg d in females.


HAEMATOLOGY
Haematology: A significant decrease in hematocrit concentration was observed, as well as in red and white blood cell counts in high dose males while females revealed a trend towards decreased erythrocyte and hematocrit values in this same group. Reticulocytes were said to be counted but the results are not presented in the publication.


CLINICAL CHEMISTRY
Clinical chemistry: High dose males showed a statistically significant decrease in AST, ALT, calcium, creatinine, and phosphorus blood parameters. Calcium and creatinine also decreased in the mid-dose males. No histopathological changes were found in the liver therefore the toxicological significance of these effects remains unclear.


ORGAN WEIGHTS
Organ weights: Relative organ weight were calculated based on total bodyweight. In high dose male animals significant decrease in relative organs weight are reported for heart, kidneys and liver. Relative brain and testes weight are increased in this group. In high dose female animals relative weight of adrenals, thymus and spleen were significantly decreased and brain weight was significantly increased in the same group. In the
other male and female dose groups no effects were noted.


GROSS PATHOLOGY
Gross pathology: Macroscopic pathology did not reveal treatment related lesions.


HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathology: In the method section of this article is stated that only the high dose and control group are examined. Due to the fact that abnormalities were observed in the high dose animals the other 2 dose groups were also examined. Microscopic pathology revealed pituitary changes characterized by cytoplasmic vacuolization of both chromophobic and acidophilic cells in the pars distalis were observed in high dose males and females. Thyroid colloid depletion was noted in both control and treated animals. This change was characterized by an increased number of smaller follicles which were lined by a prominent cuboidal epithelium but devoid of colloid. The incidence and severity was dose related in both males and females. The control group had an incidence of 30% with minimal to mild severity while those in the mid and high dose groups exhibited 100% incidence with moderate to marked severity. As no values and no statistical evaluation of this effect are presented in the publication, it is difficult to evaluate its relevance. In addition, the thyroid weight was not measured.
Dose descriptor:
NOAEL
Effect level:
55 mg/kg bw/day (nominal)
Sex:
female
Dose descriptor:
NOAEL
Effect level:
38 mg/kg bw/day (nominal)
Sex:
male
Critical effects observed:
not specified
Conclusions:
Oral administration of Sodium Chlorate for 90 days resulted in toxicologically significant effects at the mid-dose and high-dose levels in male and females. The NOAEL was for females 55 chlorate mg/kg bw/day and for males 38 chlorate mg/kg bw/day.
Executive summary:

The study was designed to investigate the systemic toxicity of the test material and complies the recommendations of the OECD Guidelines for Testing of Chemicals No. 408. The test material was administered by drinking water to three groups, each consisting of 10 Sprague-Dawley CD strain rats (male and female), for ninety consecutive days, at dose levels of 3.0 mM, 12.0 mM and 48.0 mM sodium chlorate. Two control groups of 10 rats each were dosed with either distilled water or with 48 mM saline control (sodium chloride). The final sodium concentration was 48.0 mM for each group except the distilled water control. Bodyweight, food and water consumption were monitored during the study. Haematology and clinical chemistry were evaluated at the end of the study. All animals were subjected to a gross necropsy examination and a comprehensive histopathological evaluation of tissues from test and control groups was performed. In addition, organ weights were determined.


 


One rat in the male distilled water control group died but the necropsy findings did not disclose the cause of death. No behavioural or clinical abnormalities were noted. The mean drinking water consumption varied between exposure groups from 100-200 ml/kg/day. Female exposure groups consistently drank more water (23-42%) than male exposure groups thereby receiving more chlorate/kg/day at every exposure level. The achieved doses were calculated to be: 0.36, 1.20, and 6.14 mM chlorate/kg/day in males and 0.52, 1.96 and 9.6 mM chlorate/kg/day in females (about 38, 128 and 653 mg sodium chlorate/kg/day in males and 55, 209 and 1022 mg sodium chlorate/kg/day in females). Both males and females in the high exposure groups had significant weight loss during the 90-day exposure period. Also, in these same groups females had mild but significant decreases in the following relative organ weights; adrenals, thymus and spleen, while the relative brain weight was increased. In males, the heart, kidneys and liver were mildly decreased while the brain and testes were mildly increased. Red blood cell counts and percent hematocrit were decreased in both sexes in the high dose group. Pituitary gland (pars distalis) vacuolization and thyroid gland colloid depletion were prominent in both sexes in mid and/or high dose animals.


 


Oral administration of the test material, Sodium Chlorate, to rats for a period of ninety consecutive days at dose levels of up to 1022 Chlorate mg/kg/day resulted in toxicologically significant effects at the mid-dose and high-dose levels. The “No Observed Adverse Effect Level" (NOAEL) is considered to be 55 chlorate mg/kg bw/day in females and 38 chlorate mg/kg bw/day in males.

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
See the RAAF document.
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Description (incidence and severity):
See 'Details on results'
Mortality:
mortality observed, non-treatment-related
Description (incidence):
See 'Details on results'
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
See 'Details on results'
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
See 'Details on results'
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
See 'Details on results'
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
See 'Details on results'
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
See 'Details on results'
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
See 'Details on results'
Gross pathological findings:
no effects observed
Description (incidence and severity):
See 'Details on results'
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
See 'Details on results'
Details on results:
CLINICAL SIGNS AND MORTALITY
- Number of deaths at each dose: one animals in the distilled water control group died. Necropsy findings did not reveal the cause of death. Time of death: unknown.
- During the course of chlorate exposure, no behavioural or clinical abnormalities were noted.

BODY WEIGHT AND WEIGHT GAIN
- Body weight gain: The high dose group (both sexes) also showed a significantly lower final body weight when compared to controls.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) / WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Food/water consumption: No statistically significant differences were seen in food consumption. The water consumption significantly increased in the high dose group (both sexes) as well as in the low dose group (females) and saline control group (expressed as a percentage of body weight).
Actual dose received by dose level by sex: achieved doses were calculated to be: 0.36, 1.20, and 6.14 mM chlorate ion/kg d in males and 0.52, 1.96 and 9.6 mM chlorate ion/kg d in females (about 38, 128 and 653 mg sodium chlorate/kg d in males and 55, 209 and 1022 mg sodium chlorate/kg d in females.


HAEMATOLOGY
Haematology: A significant decrease in hematocrit concentration was observed, as well as in red and white blood cell counts in high dose males while females revealed a trend towards decreased erythrocyte and hematocrit values in this same group. Reticulocytes were said to be counted but the results are not presented in the publication.


CLINICAL CHEMISTRY
Clinical chemistry: High dose males showed a statistically significant decrease in AST, ALT, calcium, creatinine, and phosphorus blood parameters. Calcium and creatinine also decreased in the mid-dose males. No histopathological changes were found in the liver therefore the toxicological significance of these effects remains unclear.


ORGAN WEIGHTS
Organ weights: Relative organ weight were calculated based on total bodyweight. In high dose male animals significant decrease in relative organs weight are reported for heart, kidneys and liver. Relative brain and testes weight are increased in this group. In high dose female animals relative weight of adrenals, thymus and spleen were significantly decreased and brain weight was significantly increased in the same group. In the
other male and female dose groups no effects were noted.


GROSS PATHOLOGY
Gross pathology: Macroscopic pathology did not reveal treatment related lesions.


HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathology: In the method section of this article is stated that only the high dose and control group are examined. Due to the fact that abnormalities were observed in the high dose animals the other 2 dose groups were also examined. Microscopic pathology revealed pituitary changes characterized by cytoplasmic vacuolization of both chromophobic and acidophilic cells in the pars distalis were observed in high dose males and females. Thyroid colloid depletion was noted in both control and treated animals. This change was characterized by an increased number of smaller follicles which were lined by a prominent cuboidal epithelium but devoid of colloid. The incidence and severity was dose related in both males and females. The control group had an incidence of 30% with minimal to mild severity while those in the mid and high dose groups exhibited 100% incidence with moderate to marked severity. As no values and no statistical evaluation of this effect are presented in the publication, it is difficult to evaluate its relevance. In addition, the thyroid weight was not measured.
Dose descriptor:
NOAEL
Effect level:
55 mg/kg bw/day (nominal)
Sex:
female
Dose descriptor:
NOAEL
Effect level:
38 mg/kg bw/day (nominal)
Sex:
male
Critical effects observed:
not specified
Conclusions:
Oral administration of Sodium Chlorate for 90 days resulted in toxicologically significant effects at the mid-dose and high-dose levels in male and females. The NOAEL was for females 55 chlorate mg/kg bw/day and for males 38 chlorate mg/kg bw/day.
Executive summary:

The study was designed to investigate the systemic toxicity of the test material and complies the recommendations of the OECD Guidelines for Testing of Chemicals No. 408. The test material was administered by drinking water to three groups, each consisting of 10 Sprague-Dawley CD strain rats (male and female), for ninety consecutive days, at dose levels of 3.0 mM, 12.0 mM and 48.0 mM sodium chlorate. Two control groups of 10 rats each were dosed with either distilled water or with 48 mM saline control (sodium chloride). The final sodium concentration was 48.0 mM for each group except the distilled water control. Bodyweight, food and water consumption were monitored during the study. Haematology and clinical chemistry were evaluated at the end of the study. All animals were subjected to a gross necropsy examination and a comprehensive histopathological evaluation of tissues from test and control groups was performed. In addition, organ weights were determined.


 


One rat in the male distilled water control group died but the necropsy findings did not disclose the cause of death. No behavioural or clinical abnormalities were noted. The mean drinking water consumption varied between exposure groups from 100-200 ml/kg/day. Female exposure groups consistently drank more water (23-42%) than male exposure groups thereby receiving more chlorate/kg/day at every exposure level. The achieved doses were calculated to be: 0.36, 1.20, and 6.14 mM chlorate/kg/day in males and 0.52, 1.96 and 9.6 mM chlorate/kg/day in females (about 38, 128 and 653 mg sodium chlorate/kg/day in males and 55, 209 and 1022 mg sodium chlorate/kg/day in females). Both males and females in the high exposure groups had significant weight loss during the 90-day exposure period. Also, in these same groups females had mild but significant decreases in the following relative organ weights; adrenals, thymus and spleen, while the relative brain weight was increased. In males, the heart, kidneys and liver were mildly decreased while the brain and testes were mildly increased. Red blood cell counts and percent hematocrit were decreased in both sexes in the high dose group. Pituitary gland (pars distalis) vacuolization and thyroid gland colloid depletion were prominent in both sexes in mid and/or high dose animals.


 


Oral administration of the test material, Sodium Chlorate, to rats for a period of ninety consecutive days at dose levels of up to 1022 Chlorate mg/kg/day resulted in toxicologically significant effects at the mid-dose and high-dose levels. The “No Observed Adverse Effect Level" (NOAEL) is considered to be 55 chlorate mg/kg bw/day in females and 38 chlorate mg/kg bw/day in males.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
18 May 1998 - 9 June 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study performed under GLP. Clinical pathology (haematology and clinical chemistry) study performed parallel with NTP 2 year drinking water study.
Principles of method if other than guideline:
Clinical pathology (haematology and clinical chemistry) study performed parallel with NTP 2 year drinking water study.
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: 5 to 6 weeks old
- Weight at study initiation: males 87 ± 1g, females 81 ± 1g.
- Fasting period before study: not applicable
- Housing: Solid-bottom polycarbonate (Lab Products, Maywood, NJ), changed twice weekly. Per cage: 5 rats
- 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: 11 (males) or 12 (females) 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: 18 May 1998 - 9 June 1998
Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
- Doses: The dose formulations were prepared once during the 3-week 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.


VEHICLE
- Justification for use and choice of vehicle (if other than water): tap water
- Concentration in vehicle: 0, 125, 250, 500, 1,000, or 2,000 mg/L
- Total volume applied: water was avalable ad libitum average water consumption males 14 (wk 1) - 21 (wk 2) g and females 12 (wk 1) - 20 (wk 2)
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 3-week studies, the dose formulations were analyzed once; all five of the dose formulations for rats and mice were within 10% of the target concentrations.
Duration of treatment / exposure:
22 days
Frequency of treatment:
daily 7/7 ad libitum water
Remarks:
Doses / Concentrations:
0, 125, 250, 500, 1,000, or 2,000 mg/L (20, 35, 75, 170, and|300 mg sodium chlorate/kg body weight per day to males and 20, 40, 75, 150, and 340 mg/kg per day to females).
Basis:

No. of animals per sex per dose:
20 (10 male and 10 female) (10 core study animals and 10 clinical pathology animals)
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: this study was used to determine the doses for the 2 year study.
- 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: Not applicable
- 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 / CLINICAL OBSERVATIONS: Yes
- Time schedule: observed twice daily and clinical findings recorded weekly


BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed initially, weekly, and at the end of the studies


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No


FOOD EFFICIENCY: No


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Water consumption was recorded weekly by cage (5 animals per cage) until day 22


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Parameters examined: (clinical pathology animals) hematocrit; hemoglobin concentration; erythrocyte, reticulocyte, and platelet counts; erythrocyte morphology; mean cell volume; mean cell hemoglobin; mean cell haemoglobin concentration; and leukocyte count and differentials


CLINICAL CHEMISTRY: Yes
- Parameters examined: (clinical pathology animals) urea nitrogen, creatinine, total protein, albumin, alanine aminotransferase; alkaline phosphatase, creatine kinase, sorbitol dehydrogenase, and bile acids


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
- Macroscopic: Necropsies were performed on all core study animals. Organs weighed were heart, right kidney, liver, lungs, right testis, and thymus of core study animals and liver of special study animals.
- Microscopic: Complete histopathology was performed on all core study control and 2,000 mg/L rats. In addition to gross lesions and tissue masses, the following tissues were examined to the no-effect level: adrenal gland, bone, brain, clitoral gland, esophagus, gallbladder (mice), 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: 7775-09-9, Carcinogenicity-rat, NTP, 2005, RS
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):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
- Mortality and time to death: 0
- Clinical signs: No clinical findings attributed to sodium chlorate exposure were observed.

BODY WEIGHT AND WEIGHT GAIN
- Body weight gain: No effect

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) / WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Drinking water concentrations of 125, 250, 500, 1,000, and 2,000 mg/L resulted in average daily doses of approximately 20, 35, 75, 170, and 300 mg sodium chlorate/kg body weight per day to male rats and 20, 40, 75, 150, and 340 mg/kg per day to female rats.
- Food/water consumption: Water consumption by exposed rats was generally similar to that by control groups throughout the study.

OPHTHALMOSCOPIC EXAMINATION
-

HAEMATOLOGY
- Haematology: An exposure concentration-related decrease in segmented neutrophil counts occurred in male and female rats on days 4 and 22. In 2,000 mg/L rats, segmented neutrophil counts were decreased by approximately 64% in males and 51% in females on day 22. The cause of the decrease is unknown, but the decrease may represent a redistribution of the neutrophils from the circulating pool to the marginal neutrophil pool. At day 22, there were minimal decreases (approximately 6%) in the hematocrit value, hemoglobin concentration, and erythrocyte count in the 2,000 mg/L males. Because it was a minimal change and occurred only in 2,000 mg/L males, this erythron decrease was not considered to be biologically or toxicologically relevant.

CLINICAL CHEMISTRY
- Clinical chemistry: No chemical-related changes in clinical chemistry parameters occurred.

URINALYSIS
-

NEUROBEHAVIOUR
-

ORGAN WEIGHTS
-

GROSS PATHOLOGY
-

HISTOPATHOLOGY: NON-NEOPLASTIC
- Histopathology: Significantly increased incidences of minimal to mild thyroid gland follicular cell hypertrophy occurred in 500 mg/L or greater males (0 mg/L, 0/10; 125 mg/L, 0/10; 250 mg/L, 1/10; 500 mg/L, 5/10; 1,000 mg/L, 10/10; 2,000 mg/L, 10/10) and females (0/10, 0/10, 1/10, 8/10, 6/10, 10/10). The thyroid gland was considered to be a target organ for sodium chlorate toxicity because of the significantly increased incidences of thyroid gland follicular cell hypertrophy in 500 mg/L or greater males and females.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
-

HISTORICAL CONTROL DATA (if applicable)
-
Dose descriptor:
NOAEL
Effect level:
35 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: minimal to mild thyroid gland follicular cell hypertrophy
Critical effects observed:
not specified
Conclusions:
Because there were no effects of sodium chlorate on survival or body weights of male or female F344/N rats, 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.
Executive summary:

As part of a two year carcinogencicity study a 3 weeks study with rats was performed to measure effects on clinical pathology (haematology and clinical chemistry). The study was performed under GLP. Groups of 10 male and 10 female core study rats and groups of 10 male and 10 female clinical pathology study rats were exposed to drinking water containing 0, 125, 250, 500, 1,000, or 2,000 mg/L sodium chlorate for 22 days. Treatment resulted in average daily doses of approximately 20, 35, 75, 170, and 300 mg sodium chlorate/ kg body weight per day for male rats and 20, 40, 75, 150, and 340 mg/kg per day for female rats. Feed and water were available ad libitum. Rats were housed five per cage. Clinical findings were recorded weekly for core study rats. Water consumption by core and special study animals was recorded weekly by cage until day 22. The animals were weighed initially, weekly, and at the end of the studies. All rats survived to the end of the study. Final mean body weights and body weight gains of all exposed groups were similar to those of the control groups. Water consumption by exposed rats was generally similar to that by control groups throughout the study. No clinical findings attributed to sodium chlorate exposure were observed. In 2,000 mg/L rats, segmented neutrophil counts were decreased by approximately 64% in males and 51% in females on day 22. At day 22, there were minimal decreases (approximately 6%) in the hematocrit value, hemoglobin concentration, and erythrocyte count in the 2,000 mg/L males. No chemical- related changes in clinical chemistry parameters occurred. Absolute and relative heart weights of 2,000 mg/L males were significantly less than those of the control group. Significantly increased incidences of minimal to mild thyroid gland follicular cell hypertrophy occurred in males and females receiving 500 mg/L or greater (males: 0 mg/L, 0/10; 125 mg/L, 0/10; 250 mg/L, 1/10; 500 mg/L, 5/10; 1,000 mg/L, 10/10; 2,000 mg/L, 10/10; females: 0/10, 0/10, 1/10, 8/10, 6/10, 10/10). Exposure Concentration Selection Rationale: Because there were no effects of sodium chlorate on survival or body weights of male or female F344/N rats, 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.

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
See the RAAF document.
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
read-across source
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):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
- Mortality and time to death: 0
- Clinical signs: No clinical findings attributed to sodium chlorate exposure were observed.

BODY WEIGHT AND WEIGHT GAIN
- Body weight gain: No effect

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) / WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Drinking water concentrations of 125, 250, 500, 1,000, and 2,000 mg/L resulted in average daily doses of approximately 20, 35, 75, 170, and 300 mg sodium chlorate/kg body weight per day to male rats and 20, 40, 75, 150, and 340 mg/kg per day to female rats.
- Food/water consumption: Water consumption by exposed rats was generally similar to that by control groups throughout the study.

OPHTHALMOSCOPIC EXAMINATION
-

HAEMATOLOGY
- Haematology: An exposure concentration-related decrease in segmented neutrophil counts occurred in male and female rats on days 4 and 22. In 2,000 mg/L rats, segmented neutrophil counts were decreased by approximately 64% in males and 51% in females on day 22. The cause of the decrease is unknown, but the decrease may represent a redistribution of the neutrophils from the circulating pool to the marginal neutrophil pool. At day 22, there were minimal decreases (approximately 6%) in the hematocrit value, hemoglobin concentration, and erythrocyte count in the 2,000 mg/L males. Because it was a minimal change and occurred only in 2,000 mg/L males, this erythron decrease was not considered to be biologically or toxicologically relevant.

CLINICAL CHEMISTRY
- Clinical chemistry: No chemical-related changes in clinical chemistry parameters occurred.

URINALYSIS
-

NEUROBEHAVIOUR
-

ORGAN WEIGHTS
-

GROSS PATHOLOGY
-

HISTOPATHOLOGY: NON-NEOPLASTIC
- Histopathology: Significantly increased incidences of minimal to mild thyroid gland follicular cell hypertrophy occurred in 500 mg/L or greater males (0 mg/L, 0/10; 125 mg/L, 0/10; 250 mg/L, 1/10; 500 mg/L, 5/10; 1,000 mg/L, 10/10; 2,000 mg/L, 10/10) and females (0/10, 0/10, 1/10, 8/10, 6/10, 10/10). The thyroid gland was considered to be a target organ for sodium chlorate toxicity because of the significantly increased incidences of thyroid gland follicular cell hypertrophy in 500 mg/L or greater males and females.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
-

HISTORICAL CONTROL DATA (if applicable)
-
Dose descriptor:
NOAEL
Effect level:
35 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: minimal to mild thyroid gland follicular cell hypertrophy
Critical effects observed:
not specified
Conclusions:
Because there were no effects of sodium chlorate on survival or body weights of male or female F344/N rats, 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.
Executive summary:

As part of a two year carcinogencicity study a 3 weeks study with rats was performed to measure effects on clinical pathology (haematology and clinical chemistry). The study was performed under GLP. Groups of 10 male and 10 female core study rats and groups of 10 male and 10 female clinical pathology study rats were exposed to drinking water containing 0, 125, 250, 500, 1,000, or 2,000 mg/L sodium chlorate for 22 days. Treatment resulted in average daily doses of approximately 20, 35, 75, 170, and 300 mg sodium chlorate/ kg body weight per day for male rats and 20, 40, 75, 150, and 340 mg/kg per day for female rats. Feed and water were available ad libitum. Rats were housed five per cage. Clinical findings were recorded weekly for core study rats. Water consumption by core and special study animals was recorded weekly by cage until day 22. The animals were weighed initially, weekly, and at the end of the studies. All rats survived to the end of the study. Final mean body weights and body weight gains of all exposed groups were similar to those of the control groups. Water consumption by exposed rats was generally similar to that by control groups throughout the study. No clinical findings attributed to sodium chlorate exposure were observed. In 2,000 mg/L rats, segmented neutrophil counts were decreased by approximately 64% in males and 51% in females on day 22. At day 22, there were minimal decreases (approximately 6%) in the hematocrit value, hemoglobin concentration, and erythrocyte count in the 2,000 mg/L males. No chemical- related changes in clinical chemistry parameters occurred. Absolute and relative heart weights of 2,000 mg/L males were significantly less than those of the control group. Significantly increased incidences of minimal to mild thyroid gland follicular cell hypertrophy occurred in males and females receiving 500 mg/L or greater (males: 0 mg/L, 0/10; 125 mg/L, 0/10; 250 mg/L, 1/10; 500 mg/L, 5/10; 1,000 mg/L, 10/10; 2,000 mg/L, 10/10; females: 0/10, 0/10, 1/10, 8/10, 6/10, 10/10). Exposure Concentration Selection Rationale: Because there were no effects of sodium chlorate on survival or body weights of male or female F344/N rats, 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.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
20 May 1998 - 11 June 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study performed under GLP. Clinical pathology (haematology and clinical chemistry) study performed parallel with NTP 2 year drinking water study.
Principles of method if other than guideline:
Clinical pathology (haematology and clinical chemistry) study performed parallel with NTP 2 year drinking water study.
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: 5 to 6 weeks old
- Weight at study initiation: males 24.5 ± 0.2g, females 19.1 ± 0.2g.
- Fasting period before study: not applicable
- Housing: Solid-bottom polycarbonate (Lab Products, Maywood, NJ), changed twice weekly. Per cage: 5 females or 1 male
- 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 (males) or 14 (females) 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: 20 May 1998 - 11 June 1998
Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
- Doses: The dose formulations were prepared once during the 3-week 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.

VEHICLE
- Justification for use and choice of vehicle (if other than water): tap water
- Concentration in vehicle: 0, 125, 250, 500, 1,000, or 2,000 mg/L
- Total volume applied: water was avalable ad libitum average water consumption males 14 (wk 1) - 21 (wk 2) g and females 12 (wk 1) - 20 (wk 2)
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 3-week studies, the dose formulations were analyzed once; all five of the dose formulations for rats and mice were within 10% of the target concentrations.
Duration of treatment / exposure:
22 days
Frequency of treatment:
7/7 daily ad libitum water
Remarks:
Doses / Concentrations:
0, 125, 250, 500, 1,000, or 2,000 mg/L in drinking water resulted in 20, 45, 90, 175, and 350 mg/kg per day to male mice and 20, 45, 95, 190, and 365 mg/kg per day to female mice
Basis:

No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: this study was used to determine the doses for the 2 year study.
- 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: Not applicable
- 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 / CLINICAL OBSERVATIONS: Yes
- Time schedule: Observed twice daily and clinical findings recorded weekly


BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed initially, weekly, and at the end of the studies


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Water consumption was recorded weekly by cage (5 animals per cage) until day 22


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Parameters examined: (clinical pathology animals) hematocrit; hemoglobin concentration; erythrocyte, reticulocyte, and platelet counts; erythrocyte morphology; mean cell volume; mean cell hemoglobin; mean cell haemoglobin concentration; and leukocyte count and differentials


CLINICAL CHEMISTRY: No


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
- Macroscopic: Necropsies were performed on all core study animals. Organs weighed were heart, right kidney, liver, lungs, right testis, and thymus of core study animals and liver of special study animals.
- Microscopic: Complete histopathology was performed on all core study control and 2,000 mg/L rats. In addition to gross lesions and tissue masses, the following tissues were examined to the no-effect level: adrenal gland, bone, brain, clitoral gland, esophagus, gallbladder (mice), 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:
No
Statistics:
See: 7775-09-9, Carcinogenicity-rat, NTP, 2005, RS
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):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
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:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
- Mortality and time to death: 0
- Clinical signs: No clinical findings attributed to sodium chlorate exposure were observed.

BODY WEIGHT AND WEIGHT GAIN
- Body weight gain: Final mean body weights and body weight gains (except bodyweight gain of 500 mg/L females) of all exposed groups of mice were similar to those of the control groups.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) / WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
- Actual dose received by dose level by sex: 0, 125, 250, 500, 1,000, or 2,000 mg/L in drinking water resulted in 20, 45, 90, 175, and 350 mg/kg per day to male mice and 20, 45, 95, 190, and 365 mg/kg per day to female mice.
- Food/water consumption: Water consumption by exposed mice was generally similar to that by the control groups throughout the study.

FOOD EFFICIENCY
-

OPHTHALMOSCOPIC EXAMINATION
-

HAEMATOLOGY
- Haematology: At the exposure concentrations selected, no chemical-related changes in haematology parameters occurred

CLINICAL CHEMISTRY
- Clinical chemistry: No abnormalities

URINALYSIS
-

NEUROBEHAVIOUR
-

ORGAN WEIGHTS
- Organ weights: There were no significant differences in organ weights between control and exposed groups

GROSS PATHOLOGY
- Gross pathology: No abnormalities

HISTOPATHOLOGY: NON-NEOPLASTIC
- Histopathology: No exposure-related lesions occurred in male or female mice.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
-

HISTORICAL CONTROL DATA (if applicable)
-
Dose descriptor:
NOAEL
Effect level:
365 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: No effects observed
Dose descriptor:
NOAEL
Effect level:
350 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: No effects observed
Critical effects observed:
not specified
Conclusions:
No exposure-related lesions occurred in male or female mice. 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.
Executive summary:

As part of a two year carcinogencicity study a 3 weeks study with mice was performed to measure effects on haematology and as a range finding study. The study was performed under GLP. Groups of 10 male and 10 female mice were exposed to drinking water containing 0, 125, 250, 500, 1,000, or 2,000 mg/L sodium chlorate for 22 days. This resulted in average daily doses of approximately 20, 45, 90, 175, and 350 mg/kg per day for male mice and 20, 45, 95, 190, and 365 mg/kg per day for female mice. No clinical findings attributed to sodium chlorate exposure were observed. At the exposure concentrations selected, no chemical related changes in hematology parameters occurred. There were no significant differences in


organ weights between control and exposed groups. No exposure-related lesions occurred in male or female mice. 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.

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
See the RAAF document.
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
read-across source
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):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
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:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
- Mortality and time to death: 0
- Clinical signs: No clinical findings attributed to sodium chlorate exposure were observed.

BODY WEIGHT AND WEIGHT GAIN
- Body weight gain: Final mean body weights and body weight gains (except bodyweight gain of 500 mg/L females) of all exposed groups of mice were similar to those of the control groups.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) / WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
- Actual dose received by dose level by sex: 0, 125, 250, 500, 1,000, or 2,000 mg/L in drinking water resulted in 20, 45, 90, 175, and 350 mg/kg per day to male mice and 20, 45, 95, 190, and 365 mg/kg per day to female mice.
- Food/water consumption: Water consumption by exposed mice was generally similar to that by the control groups throughout the study.

FOOD EFFICIENCY
-

OPHTHALMOSCOPIC EXAMINATION
-

HAEMATOLOGY
- Haematology: At the exposure concentrations selected, no chemical-related changes in haematology parameters occurred

CLINICAL CHEMISTRY
- Clinical chemistry: No abnormalities

URINALYSIS
-

NEUROBEHAVIOUR
-

ORGAN WEIGHTS
- Organ weights: There were no significant differences in organ weights between control and exposed groups

GROSS PATHOLOGY
- Gross pathology: No abnormalities

HISTOPATHOLOGY: NON-NEOPLASTIC
- Histopathology: No exposure-related lesions occurred in male or female mice.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
-

HISTORICAL CONTROL DATA (if applicable)
-
Dose descriptor:
NOAEL
Effect level:
365 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: No effects observed
Dose descriptor:
NOAEL
Effect level:
350 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: No effects observed
Critical effects observed:
not specified
Conclusions:
No exposure-related lesions occurred in male or female mice. 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.
Executive summary:

As part of a two year carcinogencicity study a 3 weeks study with mice was performed to measure effects on haematology and as a range finding study. The study was performed under GLP. Groups of 10 male and 10 female mice were exposed to drinking water containing 0, 125, 250, 500, 1,000, or 2,000 mg/L sodium chlorate for 22 days. This resulted in average daily doses of approximately 20, 45, 90, 175, and 350 mg/kg per day for male mice and 20, 45, 95, 190, and 365 mg/kg per day for female mice. No clinical findings attributed to sodium chlorate exposure were observed. At the exposure concentrations selected, no chemical related changes in hematology parameters occurred. There were no significant differences in organ weights between control and exposed groups. No exposure-related lesions occurred in male or female mice. 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.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
115 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There is no data available for potassium chlorate on repeated dose toxicity. For this endpoint studies performed with sodium chlorate were used.


 


In the sub-chronic studies performed with sodium chlorate in rats, the main target organ was the blood (with anaemia effects). The NOAEL obtained in the two studies is very similar. The GLP study reported in 1987 is more reliable as all the parameters required in Directive 2001/59/EC, Annex V, Method B.26 were evaluated and reported while in the non GLP study published in 1995 all these parameters were not reported (or incompletely reported). The thyroid effects described by McCauleyet al.(1995) at levels above 100 mg/kg bw are of uncertain clinical significance and were not observed in the rat and dog GLP studies. An increased level of thyroid colloid depletion compared to control can be regarded the result of a physiological adaptation and not an adverse effect per se. Nevertheless, similar effects were observed in chronic/carcinogenicity and fertility studies and are further explained in section 5.8.3.


 


In the 90-day study performed with sodium chlorate in the dog, there were no significant toxic effects up to the highest dose level tested. Considering that dogs have lower levels of methaemoglobin reductase than humans and thus are more susceptible to methaemoglobin, the higher NOAEL level in this studies for dogs adds to the confidence of the reliability of the 100 mg/kg NOAEL obtained in rats. The overall lowest sub-chronic NOAEL is 100 mg/kg bw/day, based on effects on erythrocytes;and a No Observed Effect Level (NOEL) of 38 mg/kg in males and 55 mg/kg in females when considering the physiological colloid depletion observed at the dose of 128 mg/kg in males and 209 mg/kg in females in the McCauley study.


 


Effect on haematology and the thyroid were also observed in a three week study with sodium chlorate in rats (NOAEL 35 mg/kg bw males and 40 mg/kg bw females) and no effects were seen in mice (NOAEL 350 mg/kg bw males and 365 mg/kg bw females) (NTP 2005).

Justification for classification or non-classification

The overall lowest sub-chronic NOAEL is 100 mg sodium chlorate/kg bw/day, based on effects on erythrocytes. On a molecular weight basis this would be 115 mg potassium chlorate/kg bw/day. These effects and this dose level do not warrant classification.


 


Other concerns for subchronic (for summary of 2-generation study see 5.9.1, NOAEL 70 mg sodium chlorate/kg bw/day corresponding to 85 mg potassium chlorate/kg bw/day) and chronic (for summary of the chronic study see 5.8, NOAEL 5 mg sodium chlorate/kg bw/day corresponding to 5.76 mg potassium chlorate/kg bw/day) chlorate exposures are related to its competitive inhibition of iodide transport through thyroid follicular cells, required for thyroid hormone synthesis. This results to an initial decrease in the T3 and T4 serum levels followed by a compensatory increase of TSH. This in turn results to an increase in thyroid cell proliferation with subsequent restored thyroid hormone production, and thus maintaining homeostasis. Thyroid effects were already visible after intake from 5 mg/kg/day in animal (rat) studies. These effects indicate a physiological compensatory mechanism to maintain homeostasis upon the presence of chlorate. This is an adaptive response to chlorate exposure. Furthermore a response to which the rat is more sensitive than human.


 


Therefore potassium chlorate is not classified for target organ specific toxicity.