Chloramide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.

Data source

Reference

Reference Type:

publication

Title:

A comparative kinetics study of monochloramine and hypochlorus acid in rat.

Author:

Abdel-Rahman M. S., Waldron D.M. and Bull R.J.

Year:

1983

Bibliographic source:

Journal of applied toxicology, vol. 3, No. 4, 175-179

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Male rats were orally administered radiolabelled forms of the test substance. Absorption and elimination until 120 h from blood were followed. In addition, distribution, excretion and metabolism were examined.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Chloramide

EC Number:

234-217-9

EC Name:

Chloramide

Cas Number:

10599-90-3

Molecular formula:

ClH2N

IUPAC Name:

chloranamine

Details on test material:

- Name of test material (as cited in study report): Monochloramine

Radiolabelling:

yes

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 data
- Weight at study initiation: 220-240 g
- Fasting period before study: yes, overnight.
- Housing: no data
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

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

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

other: not applicable

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The commercially available 36Cl-labelled HCl was used for the synthesis of monochloramine.
1) Synthesis of HO36Cl
Chlorine is produced by the reaction: 2KMnO4 + 16 HCl -> 2KCl + 2 MnCl2 + 5Cl2 + 8 H2O
H36Cl (6.66 mCi per g Cl) with a radionuclidic purity of > 99 %, was used as the source of 36Cl. The activated hydrochloric acid was then slowly injected into the reaction vessel containing 1 g of potassium permanganate. 36cl was evolved and allowed to bubble into a cylinder containing 25 ml cold distilled water. The dissolution of the chlorine was monitored with a Geiger Muller counter. The reaction was allowed to continue until apparent saturation, i.e. about 14 min past the time of initiating the reaction. Between 25 and 30 % of the Cl2 that theorically could have been produced in the reaction was actually generated and collected by this technique.
2) synthesis of Nh236Cl from HO36Cl:
HO36Cl prepared as described above was used to synthesize NH236Cl as follows: HO36cl (60 mg), which was determined by the method of Palin, 1967, from the stock solution was added to a bicarbonate buffer of pH 9.0-9.1 (13.13 g sodium bicarbonate, 1.32 g sodium carbonate per liter if water). the following equation was used to determine the amount of chlorine to be added to the buffer: a x b / c = ml stock HOCl aded to buffer.
a = desired chloramine concentration
b = final volume of chloramine solution
c = HOCl concentration (mg/l)
Concentrated ammonium hydroxide (28 % NH3) was then added according to the following equation: a x 0.0067 = ml NH4OH added.
The factor o 0.0067 provides the volume of NH4OH needed to give equimolar amounts of Cl:NH3.
The concentration of chloramine was then determined by titration according to the method of Palin, 1967. This method also detects any small amounts of chlorine or di- or tri-chloramines present in the solution. No chlorine, di- or tri-chloramines were found in the NH236Cl generated in this experiment.

Duration and frequency of treatment / exposure:

One administration

Doses / concentrations

Remarks:

Doses / Concentrations:
3 ml of 370 mg/l NH2Cl (1.1 mg per animal)

No. of animals per sex per dose / concentration:

4 males

Control animals:

not specified

Positive control reference chemical:

No

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : urine, faeces, expired air , whole blood, plasma, skin, testes, packed cells, bone marrow, kidney, lung, stomach, thyroid, thymus, duodenum, spleen, carcass, liver, ileum and fat.
- Time and frequency of sampling: Heparinized blood samples were collected by cardiac puncture at 15, 30 and 60 min and 2, 4, 8, 16, 24, 48, 72, 96 and 120h. At 120h, rats were killed by decapitation and tissue specimens were taken for determination of 36Cl. Expired air were collected using modified Roth ll-glass metabolism chambers. Fecal and urine samples were collected at 8, 16, 24, 48, 72, 96 and 120 h.

Statistics:

Not performed.

Results and discussion

Preliminary studies:

no preliminary study.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

When rats are administered 3 ml of 370 mg/l NH2Cl, a peak 36Cl plasma level (10.3 µg/l) is reached 8h following the administration. The absorption rate constant was 0.278/h with an absorption half-life of 2.5h. The 36Cl plasma level remained at plateau from 8 to 48h after administration of NH2Cl.

Details on distribution in tissues:

Distribution of 36Cl activity 120 h after the administration of NH2Cl orally: Plasma contained the highest amount (3.15 µg/g), followed by whole blood (2.66), skin (2.13), testes (2.09), packed cells (1.90), bone marrow (1.82), kidney (1.62), lung (1.58), stomach (1.53), thyroid (1.36), thymus (1.36), duodenum (1.20), spleen (1.11), carcass (0.77), liver (0.74), ileum (0.59) and fat (0.18).

Details on excretion:

During the first 24 h after NH236Cl treatment, only 0.40 and 0.08 % of the total administration dose were eliminated in the urine and feces. After the 120-h period studied for monochloramine, the proportion of administration dose eliminated through the urine was 25.15 % and through the feces was 1.98 %.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Metabolism studies revealed that NH2Cl are eliminated as chloride.

Any other information on results incl. tables

Distribution of ³⁶Cl activity in blood:

Distribution of ³⁶Cl activity in rat blood was examined 24h following the administration of NH₂³⁶Cl. In plasma, the ³⁶Cl activity was 0.87, while packed cells had an activity of 0.20 % of administration dose per ml for NH₂³⁶Cl. After washing, the packed cells twice with saline, the ³⁶Cl activity decreased to 0.06% of administration dose per ml for the NH₂³⁶Cl treated group. Following the addition of TCA to 1 ml of plasma, 0.14 % of administration dose per ml were recovered in the precipitate associated with NH₂³⁶Cl.

Subcellular distribution of ³⁶Cl compounds:

Subcellular distribution of ³⁶Cl compounds in rat liver 24 h following NH₂³⁶Cl administrationindicated that 75.0 % of total ³⁶Cl activity of the whole homogenate was recovered in the cytosol, 2.5 % in the microsomal, 1.5 % in the nuclear and <0.1 % in the mitochondrial fraction. Only 4.0 % of the total ³⁶Cl activity in the whole homogenate was found in the TCA precipitate of the homogenate following NH₂³⁶Cl treatment.

Excretion and metabolism of monochloramine:

Urine, feces and xpired air were collected over 4 and 5 day periods after the administration of 370 mg/l NH236Cl. During the first 24 h after NH236Cl treatment, only 0.40 and 0.08 % of the total administration dose were eliminated in the urine and feces. After the 120 -h period studied for NH236Cl, the proportion of administration dose eliminated through the urine was 25.15 % and through the feces was 1.98 % Metabolism studies revealed that NH236Cl are eliminated as chloride.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results

Executive summary:

In a pharmacokinetic study of NH₂³⁶Cl in Sprague-Dawley rats, kinetics for the absorption and elimination of the radiolabel were observed. An average of 83% of the radiolabel was retained 48 hours after dosing by the rats administered NH₂³⁶Cl. Peak plasma levels of chlorine (as atomic chlorine) occurred 8 hours after NH₂³⁶Cl administration. The absorption half-life of NH_2³⁶Cl was 2.5 hour and the plasma elimination half-life was 39 hours. In metabolism studies monochloramine was converted and eliminated in the chloride form, and excretion was primarily via urine. The 36 Cl was distributed throughout the major organ systems, with plasma and whole blood containing the highest concentrations. Approximately 20 % of ³⁶Cl in the plasma was bound to protein.