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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study is reliable with some restrictions. It is not performed under GLP or according to a standard guideline. The purity of the test substance or vehicle of the chemical. Potassium chlorate is used in stead of sodium chlorate, this does not influence the test results (see Details on test material).

Data source

Reference
Reference Type:
publication
Title:
The kinetics of chlorite and chlorate in rats.
Author:
Abdel-Rahman, M.S., Couri, D., Bull, R.J.
Year:
1985
Bibliographic source:
J. Environ. Path. Toxicol. Oncol. 1(6):97-103

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
No guideline followed.

Only males were on test. It was not specified whether Cl- was the only metabolite of ClO2- and Cl- and ClO2- the only metabolites of ClO3- (there was no listing of metabolites). There was no description of methods used to identify the reactive compounds. The unit of the radioactivity in tissues was not an international unit (ng/gm, assumed to be ng/g) and there were no tabulated data (only a histogram was available). The batches used for the study and their purity were not mentioned.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Potassium chlorate
EC Number:
223-289-7
EC Name:
Potassium chlorate
Cas Number:
3811-04-9
Molecular formula:
ClHO3.K
IUPAC Name:
potassium chlorate
Details on test material:
Potassium chlorate was used in stead of sodium chlorate. Labeled potassium chlorate was not commercially available and therefore it was prepared by the authors. This does not influence the test results. Because after administration to the rats ClO3 ions are formed and the excretion of radiolabeled Cl is measured.
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Duration and frequency of treatment / exposure:
A single dose was given and animals were investigated for 72 hour(s)
Doses / concentrations
Remarks:
Doses / Concentrations:
Males: 0.06 to 0.07 mg/kg bw
No. of animals per sex per dose / concentration:
Males: 8
Females: 0
Control animals:
no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
The concentration of labelled Cl was highest in the in plasma (a peak 36Cl plasma level (185 ng/mL) was reached at 30 min) followed by whole blood, stomach, testes, lung, kidney, skin, duodenum, spleen, brain, packed cells, ileum, carcass, liver and bone marrow.
Details on excretion:
The excretion was about 43% in 72h, via the urinary (40%) and faecal (3%) routes. Most of the labelled Cl (39%) was recovered during the first 24h. No radioactivity was detected in the expired air.
Toxicokinetic parameters
Toxicokinetic parameters:
half-life 1st: Elimination of 36Cl radioactivity from plasma was 35 hours after oral administration. After oral treatment with 36ClO3- there was a biphasic decline of 36Cl plasma residue levels, with successive t1/2 of 6.0 hours and 36.7 hours.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Deg. product:
The chlorate ion is eliminated as chloride (55%) and chlorite (10%).

Any other information on results incl. tables

• A peak36Cl-equivalent plasma level (470 ng/mL) was reached 2 hours after administration of36ClO2-. The half-life for the elimination36Cl from plasma was 35 hours.

 

A peak36Cl-equivalent plasma level (185 ng/mL) was reached 30 minutes after administration of36ClO3-. There was a biphasic decline of plasma residue levels, with successive t1/2of 6.0 hours and 36.7 hours.

 

• It was not possible to determine the total recovery (combining both sub-studies) as the unit of radioactivity in organs was not an international unit (ng/gm) and no percentages of the dose were given (Table B.6.1.1-1).

 

Table B.6.1.1-1: Total radioactive residues and total recovery at 72 hours

 

 

 

Total radioactive residues (percent of administered dose)

Treatment schedule

36ClO2-

36ClO3-

Dose-level ranges (mg/kg) RMS

0.12-0.14

0.06-0.07

Sub-study 2

Urine

34.51

40.13

Faeces

4.75

3.14

Cage wash

Not performed

Exhaled air14CO2

0

0

 

Total excreted

39.26

43.27

Sub-study 1

Total retained in tissues, organs and carcass

ND

ND

 

Total recovery

-

-

ND: not expressed as percent of the dose.

-: the total recovery could not be calculated.

 

Cumulated excretions of radioactivity in urine and faeces are summarized in table B.6.1-2.

 

Table B.6.1.1-2: Excretion of radioactivity (expressed as % of the administered dose) in urine and faeces after oral administration of36ClO2-or36ClO3-to male rats

 

Total radioactive residues (percent of administered dose)

Treatment schedule

36ClO2-

36ClO3-

Dose-level ranges (mg/kg) RMS

0.12-0.14

0.06-0.07

Time of collection

urine

faeces

total

urine

faeces

total

0-8 h

3.00

 

3.00

21.57

 

21.57

8-16 h

6.38

6.38

6.23

6.23

16-24h

4.45

4.45

8.63

8.63

0-24 h

13.83

0.87

14.7

36.43

2.47

38.90

24-48 h

8.46

2.42

10.88

0.98

0.30

1.28

48-72 h

12.23

1.46

13.69

2.73

0.37

3.10

0-72 h (total)

34.51

4.75

39.26

40.14

3.14

43.28

 

• The actual absorbed fraction could not be determined as total recovery was unknown (radioactivity in tissues, organs and carcass was not expressed as percent of the administered dose, and radioactivity in cage washes was not measured).

 

Distribution:

 

• After oral administration of36ClO2-, the highest concentration was measured (in decreased order) in whole blood, packed cells, plasma, stomach, testes, skin , lungs, kidney, duodenum, carcass ileum brain, bone marrow and liver.

After oral administration of36ClO3-, the highest concentration was measured (in decreased order) in plasma, whole blood, stomach, testes, lung, kidney, skin , duodenum, spleen, brain, packed cells, carcass, liver and bone marrow, with a 4 order magnitude factor between the smallest and the highest concentrations in tissues.

NB: unit provided in the report was an unknown unit (ng/gm, assumed by the RMS to be ng/g). There were no tabulated data, only a diagram.

 

• After36ClO2-treatment,36Cl radioactivity was detected in urines and faeces. However, it was not possible to state if36Cl radioactivity found in faeces was unchanged36ClO2-or metabolites. In urine,36ClO2-was excreted unchanged and as36Cl-(Table B.6.1.1-3).

After36ClO3-treatment,36Cl radioactivity was detected in urines and faeces. However, it was not possible to state if36Cl radioactivity found in faeces was unchanged36ClO3-or metabolites. In urine,36ClO3-was excreted unchanged and as36ClO2-and36Cl-(B.6.1.1-3).

No radioactivity was detected in the expired air over 72 hours, after36ClO2-and36ClO3-treatments.

The total radioactivity found in urine was slightly different from the sum of radioactivity as unchanged parent and metabolites in urine: 34.51vs. 37.60% after36ClO2-treatment, and 40.14vs. 37.60 after36ClO3-treatment.

 

Table B.6.1.1-3: Distribution of urinary radioactivity expressed as % of the administered dose over 72 hours

 

Total radioactive residues

(percent of administered dose)

Treatment schedule

36ClO2-

36ClO3-

Dose-level ranges (mg/kg) RMS

0.12-0.14

0.06-0.07

36Cl-

31.55

20.49

36ClO2-

6.05#

3.905

36ClO3-

-

13.2#

Total

37.60

37.60

#: parent compound.

Applicant's summary and conclusion

Conclusions:
No bioaccumulation potential based on study results
Oral absorption of chlorates is fast since a peak is reached in 30 minutes. The total recovery and the actual oral absorption could not be determined because of inadequate data reporting (organs, tissues and carcass) and absence of measure of radioactivity in cage wash. An estimate of oral absorption could be the percent of administered dose found in urine (34.51% for 36ClO2- treatment and 40.13% for 36ClO3- treatment).
The half-life for the elimination of 36Cl radioactivity from plasma was 35 hours after oral administration of 36ClO2-. After oral treatment with 36ClO3- there was a biphasic decline of 36Cl plasma residue levels, with successive t1/2 of 6.0 hours and 36.7 hours. For both test items, the routes of excretion were faeces and urine (no excretion by expired air).
In urine, 36ClO2- was mainly excreted as Cl- (32% of the dose) and to a lesser extent in unchanged form (6% of the dose). In urine, 36ClO3- was mainly excreted as Cl- (20% of the dose), followed by unchanged parent (13% of the dose) and 36ClO2- (4% of the dose).
Executive summary:

Abdel-Rahman et al. (1985) determined the kinetics of chlorate (and chlorite) in rats. The test material was labelled potassium chlorate K36ClO3. No information was supplied on batch No., purity or vehicle of the chemical. Two groups of four male Sprague Dawley rats received an oral dose of 3 mL of a 5 mg/L36ClO3-(0.85 µCi) (0.06 -0.07 mg/kg bw) preparation. Heparinized blood samples were taken from the first group at 5, 10, 20, 30 and 60 min and 2, 4, 8, 24 and 48 h by orbital sinus puncture and at 72 h when the rats were sacrificed by decapitation. Tissue specimens were taken from the stomach, testes, lung, kidney, duodenum, ileum, spleen, liver, brain, bone marrow, carcass and skin. Faecal, urine and expired air samples were taken from the second group of rats after 8, 16, 24, 48 and 72 h. Radioactivity was measured in all the samples taken.

After administrating of 3 mL of 5 mg/L36ClO3-to the rats, a peak36Cl plasma level (185 ng/mL) was reached at 30 min, showing that absorption is rapid. The half-life for the elimination of36Cl radioactivity from plasma was 35 hours after oral administration of36ClO2-. After oral treatment with36ClO3-there was a biphasic decline of36Cl plasma residue levels, with successive t1/2of 6.0 hours and 36.7 hours. For both test items, the routes of excretion were faeces and urine (no excretion by expired air). T

he distribution of36Cl-compounds 72 h after administration was highest in plasma followed by whole blood, stomach, testes, lung, kidney, skin, duodenum, spleen, brain, packed cells, ileum, carcass, liver and bone marrow. The excretion after chlorate administration was about 43% of administered dose in the 72-hour period, via urinary (40%) and faecal (3%) routes. Most of the36Cl-(39% of administered dose) was recovered during the first 24 hours.

In urine,36ClO2-was mainly excreted as Cl-(32% of the dose) and to a lesser extent in unchanged form (6% of the dose). In urine,36ClO3-was mainly excreted as Cl-(20% of the dose), followed by unchanged parent (13% of the dose) and36ClO2-(4% of the dose).