Potassium perchlorate

Basic toxicokinetics

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: Non-guideline study

Data source

Reference

Reference Type:

publication

Title:

The Metabolism of Perchlorate in the Rat

Author:

Goldman SJ & Stanbury JB

Year:

1973

Bibliographic source:

Endocrinology 92: 1536

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The disposal of potassium perchlorate was studied in rats maintained on low iodine diet.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Potassium perchlorate

EC Number:

231-912-9

EC Name:

Potassium perchlorate

Cas Number:

7778-74-7

Molecular formula:

ClHO4.K

IUPAC Name:

potassium perchlorate

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report):potassium perchlorate K36ClO2
- Molecular formula (if other than submission substance):K36ClO2

- Substance type:
- Physical state:
- Analytical purity: no data

- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Radiochemical purity (if radiolabelling): no information
- Specific activity (if radiolabelling): 240µCi/mmole
- Locations of the label (if radiolabelling): 36Cl
- Expiration date of radiochemical substance (if radiolabelling): no data
- Stability under test conditions: stable for duration of the assay
- Storage condition of test material: no data

Radiolabelling:

yes

Remarks:

perchlorate labelled with 36Cl

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no information
- Weight at study initiation: Group 1 - 24 rats weighing between 200 and 250g. Group 2 - 20 rats weighing between 300 and 350g.
- Fasting period before study: Group 1 was maintained on low iodine diet for 5 weeks prior to first administration of potassium perchlorate. Group 2 was maintained on low iodine diet for 4.5 weeks prior to first administration of potassium perchlorate.
- Housing: No information
- Individual metabolism cages: no data
- Diet (e.g. ad libitum): Remington diet (low iodine), provided by General Biochemical Inc., Chagrin Falls, Ohio , available ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: circa 4-5 weeks on Remington diet before dosing initiated

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no information
- Humidity (%): no information
- Air changes (per hr): no information
- Photoperiod (hrs dark / hrs light): no information

IN-LIFE DATES: From: no information To: no information

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

physiological saline

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Radiolabelled potassium perchlorate with specific activity of 240 µCi/mmole prepared in 1 mL of saline solution and injected as a 0.1 µCi dose (approximately 40 µg of stable perchlorate per injection)

DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle:
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):
- Purity:

HOMOGENEITY AND STABILITY OF TEST MATERIAL:

Duration and frequency of treatment / exposure:

In Group 1 the four subgroups were terminated 2, 8, 24 and 48 h after dosing.

In Group 2 three of the four subgroups were treated the same as Group 1 and then terminated 2, 8 or 24 h after dosing. The fourth subgroup was dosed at 0.2 µCi/mmole and terminated after 96 hours

Doses / concentrations

Remarks:

Doses / Concentrations:
0.1 µCi/mmole and 0.2 µCi/mmole

No. of animals per sex per dose / concentration:

Group 1 - 4 subgroups each consisting of six male rats

Group 2 - 4 subgroups each consisting of five male rats

Control animals:

no

Positive control reference chemical:

No information

Details on study design:

- Dose selection rationale: perchlorate anions competitively inhibit uptake of iodine by the thyroid in both rats and humans; and discharge accumulated iodide not covalently bound in organic form. Perchlorate is selectively concentated by rats in the thyroid but undergoes no chemical change between injection and excretion and is therefore a good biological marker for thyroid uptake and tissue distribution models and selective uptake reduces the required concentration. Two dose levels, 0.1 and0.2 µCi/mmole, were selected.

Details on dosing and sampling:

Tissue samples obtained from Group 2 subgroup 4 included thyroid, kidney, spleen, liver and brain.

Urine samples were collected over 24 hour intervals up to 96 hours after dosing (Group 2, subgroup 4)

Statistics:

No data

Results and discussion

Preliminary studies:

No information

Toxicokinetic / pharmacokinetic studies

Details on absorption:

No information

Details on distribution in tissues:

No accumulation ofradionuclide in liver, brain, kidneys or spleen. Maximum concentration in thyroid was achieved afte 4 hours. Rates of disappearance from thyroid and plasma, and rate of appearance in urine, were exponential with a half-time of circa 20 hours.

Details on excretion:

Rates of disappearance from thyroid and plasma, and rate of appearance in urine, were exponential with a half-time of 20 hours.

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

No information

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

No data

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Following intraperitoneal administration to rats, maximal thyroid concentration was attained approximately 4 hours after dosing. Maximum concentration was 2.5 % of the dose per g of tissue. All of th radionuclide in the thyroid was soluble in trichloracetc acid. No significant concentration of radionuclide was recovered from kidney, liver,spleen or brain tissue. The rate of disappearance from plasma or from thyroid and the rate of appearance in urine were all exponential, with half-times of circa 20 hours. These disposal rates were similar to rates calculated for radiolabelled iodide by other workers.

Executive summary:

The disposal of potassium perchlorate was studied in rats maintained on low iodine diet. Following intraperitoneal injection the radionuclide levels were monitored in the thyroid. Radionuclide levels were also monitored in kidney, liver, brain and spleen. Radionuclide disappearance rates from plasma and thyroid were measured together with the appearance rate in urine. Half life times were calculated for various rates.

Perchlorate displacement of iodide in rat thyroid has been widely used in therapeutic situations, blocking iodide entry into the thyroid or discharging previously accumulated, non-covalently bound iodide (e.g. in patients with Pendred's syndrome). The use of radiolabelled perchlorate in the current assay demonstated low levels of thyroid uptake at the specific activities used, no evidence of covalent binding of the radionuclide in the thyroid, no selective retention of the radionuclide in the examined tissues and exponential disappearance from the body with a half life of 20 hours.

The authors indicate that the current tests used the lowest radiolabelled perchorate dose consistent with adequate counting rates and the highest specific activities. Calculating radiation doses for administration to man by reference to the behaviour of

radiolabelled perchlorate appears reasonable based on the metabolic similarities to iodide and disposal and retention properties being similar to iodide when covalent binding of iodide is blocked.

Following intraperitoneal administration to rats, maximal thyroid concentration was attained approximately 4 hours after dosing. Maximum concentration was 2.5 % of the dose per g of tissue. All of th radionuclide in the thyroid was soluble in trichloracetc acid. No significant concentration of radionuclide was recovered from kidney, liver,spleen or brain tissue. The rate of disappearance from plasma or from thyroid and the rate of appearance in urine were all exponential, with half-times of circa 20 hours. These disposal rates were similar to rates calculated for radiolabelled iodide by other workers.