Administrative data

Purpose flag:
weight of evidence
Study result type:
experimental result
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
The study is performed similarly to the OECD guideline No. 417, but it is not a GLP study and there is no detailed information on the study design.




Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1982

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
: only male rats tested, no information on the toxicity of the treatment.
Methods:
in vivo
Principles of method if other than guideline:
not applicable.
GLP compliance:
no data
Objective of studyopen allclose all

Test materials

Identity of test material same as for substance defined in section 1 (if not read-across):
yes
Test material identityopen allclose all
Details on test material:
- Name of test material (as cited in study report): chlorine Dioxide
- Specific activity of 36ClO2 : 0.7 μCi
- Physical state: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Stability under test conditions: assumed to be stable during the test (sponsor responsibility)
- Storage condition of test material: no data
- Other: The generation of 36ClO2 from K36ClO3 was accomplished by the following reaction: 2K36ClO3 + (COOH)2 + 2H2SO4  236ClO2 + 2KHSO4 + 2CO2 + 2H2O. The 36ClO2 gas was trapped in ice cold water.
Radiolabelling:
yes
Remarks:
36Cl

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
Weight at study initiation: 230 +/- 20 g

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
no data
Details on exposure:
no details
Duration and frequency of treatment / exposure:
single administration
Doses / concentrations:
1.5 mg/kg bw 
No. of animals per sex per dose:
4 animals/group
Control animals:
no data
Positive control:
no positive control
Details on study design:
no details
Details on dosing and sampling:
Sampling time:
Heparinized blood samples were collected at 5, 10, 20, 30 and 60 min and 2, 4, 8, 24 and 48 h and at termination at 72 h. At 72h , rats were killed by decapitation, and blood was collected in heparinized tubes.
In another set of experiments, expired air, faecal and urine samples were collected.

Samples:
Blood samples were collected from the orbital sinus. Tissue specimens of stomach, testes, lung, kidney, duodenum, ileum, spleen, liver, bone marrow, carcass and skin were taken.
In another set of experiments, rats were housed in Roth all glass metabolism chambers for the collection of expired air, faecal and urine samples. 

Analyses:
Tissue specimens were prepared for the determination of 36chlorine content by liquid scintillation spectrometry.
Statistics:
no data

Results and discussion

Preliminary studies:
not applicable

Pharmacokinetic studies

Details on absorption:
The rate constant for absorption was highest for 36ClO2 (3.77 +/- 0.24 /hr), followed by 36 ClO3-, 36ClO2-. The T1/2 for absorption, which is inversely proportional to the rate constant, was shortest for 36 ClO2 (0.18 +/- 0.01 hr). For 36ClO2, the rate constant for elimination from plasma was 0.0158 ± 0.0008 h-1and the half life was 43.9 ± 2.3 h. For 36ClO2-, the rate constant for elimination from plasma was 0.0197 ± 0.0017 h-1 and the half life was 35.2 ± 3.0 h. 
Details on distribution in tissues:
The distribution of 36ClO2 was highest in the kidney followed by lung, plasma, stomach, ileum, liver, duodenum, spleen and bone marrow. The distribution of 36ClO2- was highest in whole blood, followed by packed cells, plasma, stomach, testes, skin, lung, duodenum, kidney, carcass, spleen, ileum, bone marrow and liver.
When plasma was separated from packed cells, radioactivity was divided evenly between the plasma and packed cells (0.55 ± 0.038 and 0.63 ± 0.11% for initial dose, respectively) for ClO2-.
See details in Table 7.1.1/1.
Details on excretion:
In the case of 36ClO2, 75% of the recovered dose was found in the urine, while 25% was found in the faeces. For 36ClO2-, 87 and 13% was found in urine and faeces respectively. 36Cl compounds were not found in expired air of any treatment group throughout the 72 h time period.
Toxicokinetic parametersopen allclose all

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
The administered 36Cl compounds are found as various metabolites in rat urine. After 72 h from the time of administration, 36ClO2 is found in urine as Cl-, ClO2- and ClO3-. Cl- is the major metabolite (approx. 87 % of total radioactivity found in urine).

Bioaccessibility

Any other information on results incl. tables:
Table 7.1.1/1:Distribution of chlorine dioxide in different tissues 72 hrs after an administration of 100 mg/L
Tissue
Concentration of36ClO2after an administration of 100 mg/L*
plasma
0.72 +/- 0.02
Packed cells
-
Whole blood
-
Kidney            
0.81 +/- 0.15
Lung
0.74 +/- 0.15
Stomach
0.70 +/- 0.15
Deodenum
0.29 +/- 0.07
Ileum
0.48 +/- 0.09
Liver
0.38 +/- 0.09
Spleen
0.25 +/- 0.04
Bone marrow
0.16 +/- 0.03
Testes
-
Skin
-
Carcass
-
*: values are expressed as a percentage of the initial dose from 4 rats 72 hrs after the treatment.
Table 7.1.1/2: Metabolism of chlorine dioxide, chlorite and chlorate in rat urine
Treatment
Cl-*
ClO2-*
ClO3-*
36ClO2(100 mg/L)
26.93 ± 1.6
3.46 ± 1.0
0.73 ± 0.73
36ClO2-(100 mg/L)
31.55 ± 4.5
6.0 ± 0.6
-
36ClO3-(5 mg/L)
20.50 ± 0.7
3.95 ± 2.7
8.2 ± 2.9
*: values are expressed as a percentage of the initial dose from 4 rats 72 hrs after the treatment.

Applicant's summary and conclusion

Conclusions:
Radioactivity was rapidly absorbed from the gastrointestinal tract following oral administration of 36ClO2 and the half time for elimination of 36Cl from the rat was 44 h, corresponding to a rate constant of 0.016/h.  After 72 h, radioactivity was highest in kidney followed by lung, plasma, stomach, ileum, liver, duodenum, spleen and bone marrow. 36Cl in plasma peaked at 2 h after oral administration of 36ClO2-. 36Cl excretion in the case of ClO2- probably represented saturation of the biotransformation and excretion pathway. An even distribution in packed cells compared to plasma was detected in chlorite treatment.
Executive summary:
In this toxicokinetics study, radiolabelled Chlorine Dioxide (36ClO2),was administered to Sprague-Dawley rats (4 males/dose) by gavage, at a dose level of 100 mg/L producing a dose of 1.5 mg/kg bw of test substance. In parallel, chlorite or chlorate were also administered by oral route.
The metabolism and pharmacokinetics of chlorine dioxide and chlorite were examined. Heparinized blood samples were collected at 5, 10, 20, 30 and 60 min and 2, 4, 8, 24 and 48 h and at termination at 72 h. In another set of experiments, expired air, faecal and urine samples were collected.
The rate constants for absorption of 36ClO2 and 36ClO2- were 3.77 ± 0.24 h-1 and 0.198 ± 0.06 h-1, respectively. The half lives for absorption of 36ClO2 and 36ClO2- were therefore 0.18 ± 0.01 h and 3.50 ± 1.06 h, respectively. For 36ClO2, the rate constant for elimination from plasma was 0.0158 ± 0.0008 h-1 and the half life was 43.9 ± 2.3 h. For 36ClO2-, the rate constant for elimination from plasma was 0.0197 ± 0.0017 h-1 and the half life was 35.2 ± 3.0 h.
The distribution of  36ClO2 was highest in the kidney followed by lung, plasma, stomach, ileum, liver, duodenum, spleen and bone marrow. The distribution of  36ClO2-was highest in whole blood, followed by packed cells, plasma, stomach, testes, skin, lung, duodenum, kidney, carcass, spleen, ileum, bone marrow and liver.
In the case of 36ClO2 treatment, 75% of the recovered dose was found in the urine, while 25% was found in the faeces. For 36ClO2- treatment, 87 and 13% was found in urine and faeces respectively. 36Cl compounds were not found in expired air of any treatment group throughout the 72 h time period.

After 72 h from the time of administration,36ClO2 was found in urine as Cl-, ClO2-and ClO3-whereas36ClO2- is found as Cl-and ClO2-. In all three cases, Cl- is the major metabolite (approximately 87 and 84 % of the total radioactivity found in urine for 36ClO2 and 36ClO2-treatment, respectively).