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Toxicological information

Repeated dose toxicity: oral

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Administrative data

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.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report Date:
1987

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
EPA OPP 82-1 (90-Day Oral Toxicity)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Sodium Chlorate, 100% Active Ingredient, received from Kerr McGee Chemicals
Corporation
- Physical state: white granualr solid
- Analytical purity: documented by the sponsor
- Composition of test material, percentage of components: documented by the sponsor
- Purity test date: no info
- Lot/batch No.: no info
- Stability under test conditions: determined by the sponsor
- Storage condition of test material: in tightly sealed, light-resistent containers in a temperature monitored room
- Other: date received: November 25, 1986

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals 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

Administration / exposure

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)
Doses / concentrations
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

Examinations

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.

Results and discussion

Results of examinations

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

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Sex:
male/female
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.