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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
No GLP information. Data on residues, metabolism and excretion in rats.

Data source

Reference
Reference Type:
publication
Title:
Tissue Residues, Metabolism, and Excretion of Radiolabeled Sodium Chlorate (Na(36Cl)O3) in Rats
Author:
Hakk H, Smith DJ and Shappell NW
Year:
2007
Bibliographic source:
J. Agric. Food Chem. 55, 2034-2042

Materials and methods

Objective of study:
distribution
excretion
metabolism
Principles of method if other than guideline:
A toxicokinetics study of sodium chlorate was carried out with a group of 4 male Sprague-Dawley rats. A single oral dose of 1mg/rat of radiolabeled sodium chlorate (Na36ClO3) was administrated by gavage. Urine, feces and respired air were collected during 72 hours. After this period each rat was anesthetized and exsanguineted and dissected. An epididymal adipose tissue, bone (femur), brain, diaphragm, GI tract, heart, kidney, liver, lungs, skin, spleen, testes, and thymus were removed, weighed and analyzed. A control group of 2 rats was included in the study.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Sodium Chlorate
- Radiochemical purity (if radiolabelling): 94.4%
- Locations of the label (if radiolabelling): Chlorine
- Specific activity (if radiolabelling): 0.575 mCi/mmol
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Sprague-Dawley (Indianapolis)
- Weight at study initiation: 349 ± 25.8 g
- Fasting period before study: rats were allowed to ad libitum access to feed and water before the prestudy
- Housing: Hanging in glass metabolism cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): diet and water ad libitum
- Acclimation period: yes

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Sodium (36Cl) chlorate was dissolved in water (2.0 mg/mL).

VEHICLE
- Concentration in vehicle: (2.0 mg/mL)

Duration and frequency of treatment / exposure:
The duration of the treatment was 72 hours.
Rats received a single oral dose.
Doses / concentrations
Dose / conc.:
3 mg/kg bw (total dose)
Remarks:
A single dose of 0.5 mL (1 mg per rat or roughly 3 mg/kg)
No. of animals per sex per dose:
4 male rats / dose
Control animals:
yes, concurrent no treatment
Positive control:
Positive control was not included
Details on study design:
- Dose selection rationale: The target dose was approximately 1 mg per rat (or roughly 3 mg/kg). This dose was about 10-fold less than sodium chlorate doses (on a mg/kg body weight basis) shown to be effective at reducing pathogens in livestock species (40 mg/kg in cattle and 35 mg/kg in swine).

Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, respired air, blood, brain, bone, epididymal adipose tissue, diaphragm, GI tract, heart, kidney, liver, lung, muscle, plasma, skin, spleen, testes, carcass remains and thymus.

- Time and frequency of sampling:
Excreta samples were collected at 6 h interval for the first 24 h, 8 h intervals for the second 24 h and 12 h intervals for the last 24 h of the study.
Respired gases were collected during the whole collection period and the hydroxide and the water traps were sampled at the end of the 72 h study period.
After the 72 h period, each rat was anesthetised and exsanguinated via heart puncture. Blood was drawn into heparinised syringes. A 1 ml aliquot of whole blood was removed and frozen and the remainder was processed for plasma.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): urine, liver, kidney, muscle, carcass tissues, cage washes and bile.
- Time and frequency of sampling: Excrete samples were collected at 6 h interval for the first 24 h, 8 h intervals for the second 24 h and 12 h intervals for the last 24 h of the study.
- From how many animals: (samples pooled or not) 4 animals
- Limits of detection and quantification: yes, the LOD was defined as the mean background dpm plus three standard deviation of the mean.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
After an orally administered [36Cl] chlorate dose, the data show that radioactivity was rapidly absorbed and excreted, mainly in the urine of animals. Only 12.3 ± 7.9% of the radioactivity remained in the bodies of male rats at 72 h.
Details on distribution in tissues:
Tissues with the highest percentages of the administered radiochlorine were carcass remains (4.6 ± 2.9%), skin (3.2 ± 1.9%), and gastrointestinal
tract (1.3 ± 1.1%). No other tissues contained greater than 1% of the administered radiochlorine.
Details on excretion:
Urine was the major route of radiochlorine excretion (79% of total). The greatest amount of radiochlorine excreted was generally observed in urine samples collected in the earliest interval (0 – 6 hours).
Feces were a minor excretory route (less than 1% was eliminated in feces each day)

Any other information on results incl. tables

Disposition, Elimination, and Total Recovery of Radiochlorine (% of Dose) in Rats Orally Dosed with [36Cl] chlorate (Table 1)

Table 1

Animal

 

rat 5

rat19

rat26

rat27

mean

SD

tissues

21.9

4.5

15.4

7.5

12.3

7.9

 

 

feces

 

 

 

0-24 h

3.0

0.05

0.04

0.6

0.9

1.4

24-48 h

1.5

0.03

0.09

0.3

0.5

0.7

48-72 h

0.6

0.06

0.1

0.5

0.3

0.3

total

5.1

0.1

0.2

1.4

1.7

2.3

 

 

urine

 

 

 

0-6 h

9.4

45.8

32.5

56.7

36.1

20.4

6-12 h

27.2

32.7

27.9

17.2

26.3

6.5

12-18h

9.0

5.5

5.1

3.8

5.8

2.2

18-24h

4.1

2.2

1.9

1.1

2.3

1.3

24-32 h

1.5

1.8

1.2

1.1

1.4

0.3

32-40 h

2.3

1.0

1.5

0.9

1.4

0.7

40-48 h

3.1

0.2

2.5

0.6

1.6

1.4

48-60 h

2.9

0.7

2.8

1.0

1.8

1.1

60-72 h

5.1

0.5

2.6

1.1

2.4

2.1

total

64.6

90.4

78.0

83.5

79.1

10.9

expiratory gases

0.0

0.0

0.0

0.0

0.0

0.0

cage rinse

1.4

0.3

2.2

1.3

1.3

0.8

total recovery

93.0

95.3

95.7

93.7

94.4

1.3

 

 

Concentrations of Radioactive Residues (ppm Fresh Tissue Weight; Chlorate Equivalents) in Tissues of Rats Dosed Orally with [36Cl] chlorate and Slaughtered 72 h after Dosing (Table 2)

 

Table 2

 

rat 5

rat 19

rat 26

rat27

 

 

tissue

(ppm)

(ppm)

(ppm)

(ppm)

mean

SD

adipose tissue

0.28

0.05

0.08

0.05

0.17

0.10

blood

1.17

0.29

1.09

0.50

0.76

0.43

brain

0.53

0.14

0.52

0.22

0.35

0.20

bone

0.34

0.10

0.35

0.16

0.24

0.13

diaphragm

0.51

0.10

0.36

0.16

0.28

0.19

GI tract

0.61

0.12

0.46

0.20

0.35

0.23

heart

0.53

0.14

0.46

0.23

0.34

0.18

kidney

0.68

0.18

0.67

0.28

0.45

0.26

liver

0.45

0.12

0.40

0.18

0.29

0.16

lung

0.95

0.24

0.86

0.40

0.61

0.35

muscle

0.21

0.06

0.20

0.10

0.14

0.08

plasma

1.43

0.36

1.36

0.62

0.94

0.53

skin

0.62

0.18

0.52

0.27

0.40

0.20

spleen

0.66

0.17

0.56

0.27

0.42

0.23

testes

1.04

0.27

0.90

0.45

0.66

0.36

carcass remains

0.35

0.09

0.34

0.15

0.24

0.13

thymus

0.59

0.17

0.60

0.27

0.41

0.22

 

  

Speciation of Total Radioactive Residues in Livers, Kidneys, Muscle, and Carcass Remains of Rats Orally Dosed with [36Cl] chlorate and of Tissues from Control Rats Fortified with a [36Cl] chlorite, [36Cl]chlorate Standarda(Table 3)

 

Table 3

tissue

dosed tissue residueb

fortified tissue residuec

Cl-(%)

ClO3-(%)

Cl-(%)

ClO3-(%)

liver

100

0

59.6

40.3

kidney

100

0

52.5

47.5

muscle

99.8

0.2

53.1

46.9

carcass remains

98.1

1.9

48.1

51.9

aChlorite was not detected in any tissue.

bComposition of residue recovered from tissues of rats dosed with chlorate;n= 4, duplicate analyses.

cComposition of residue recovered from fortified control tissue (fortification composition was 52.3% chloride, 47.9% chlorate; duplicate analyses per tissue).

Applicant's summary and conclusion

Conclusions:
The [36Cl] chlorate dose was rapidly absorbed and excreted, mainly in the urine of animals. Only 12.3 ± 7.9% of the radioactivity remained in the bodies of male rats at 72 h. Tissues with the highest percentages of the administered radiochlorine were carcass remains, skin and gastrointestinal tract. No other tissues contained greater than 1% of the administered radiochlorine. Chlorate is rapidly adsorbed and reduced to chloride.
Executive summary:

A toxicokinetics study of sodium chlorate was carried out with a group of 4 male Sprague-Dawley rats. A single oral dose of 1 mg/rat of radiolabeled sodium chlorate (Na36ClO3) was administrated by gavage. Urine, feces and respired air were collected during 72 hours. After this period each rat was anesthetized and exsanguineted and dissected. An epididymal adipose tissue, bone (femur), brain, diaphragm, GI tract, heart, kidney, liver, lungs, skin, spleen, testes, and thymus were removed, weighed and analyzed. A control group of 2 rats was included in the study. The results obtained were: The [36Cl] chlorate dose was rapidly absorbed and excreted, mainly in the urine of animals. Only 12.3 ± 7.9% of the radioactivity remained in the bodies of male rats at 72 h. Tissues with the highest percentages of the administered radiochlorine were carcass remains, skin and gastrointestinal tract. No other tissues contained greater than 1% of the administered radiochlorine. Chlorate is rapidly adsorbed and reduced to chloride.