Reaction mass of tetramethylammonium hypochlorite and tetramethylammonium chloride

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

This study is considered reliable with restrictions since the study was conducted prior to GLP and internationally accepted test guidelines, but the study is well documented and scientifically acceptable. Read-across justification: The target substance is a reaction mass from blending of two components (bentzotriazole solid and 25 % tetramethylammonium hydroxide water solution) followed by reaction with chlorine gas. The main constituent of this multi-constituent are tetramethylammonium hypochlorite and tetramethylammonium chloride. Based on the chemical structure and chemical reactions of chlorine compounds the target substance and the source substances (chlorinated bleaching agents such as sodium hypochlorite) meet the same toxicological behaviour in the physiological conditions. Their irritation and skin sensitisation as well as acute and long-term adverse effects to human health are similar. Therefore, and in order to avoid the unnecessary animal testing, the read-across data from sodium hypochlorite and chlorine is used to evaluate the toxicokinetics, the genetic toxicity, the sensitisation potential of the target substance.

Data source

Reference

Reference Type:

publication

Title:

A Comparative Kinetics Study of Monochloramine and Hypochlorous Acid in Rat

Author:

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

Year:

1983

Bibliographic source:

Journal of Applied Toxicology, Vol 3

Materials and methods

Objective of study:

toxicokinetics

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Hypochlorous acid

EC Number:

232-232-5

EC Name:

Hypochlorous acid

Cas Number:

7790-92-3

IUPAC Name:

hypochlorous acid

Details on test material:

Hypochlorous acid: 2190 dpm (= 0.99nCi) /ug 36Cl
Hypochlorous acid: 1340 dpm (= 0.60nCi) /ug 36Cl

Radiolabelling:

yes

Remarks:

HO36Cl

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

Weight: 220-240 g

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Group 1: 3 ml of 250mg/L HO36Cl (0.75mg/animal); blood kinetics
Group 2: 3 ml of 200mg/L HO36Cl (0.60mg/animal); biodistribution study
Group 3: 3 ml of 200mg/L HO36Cl (0.60mg/animal); housing in metabolic chambers and collection of expired air, feces and urine

Duration and frequency of treatment / exposure:

Single dose

Doses / concentrations

Remarks:

Doses / Concentrations:
Group 1: Single dose of approximately 3.27 mg/kg bw (non-fasted)

Group 2 and 3: Single dose of approximately 2.62 mg/kg bw (fasted overnight)

Specific activity
Group 1: 1340 dpm/µg 36Cl, 0.60 nCi/µg
Group 2: 2190 dpm/µg 36Cl, 0.99 nCi/µg
Group 3: 2190 dpm/µg 36Cl, 0.99 nCi/µg

No. of animals per sex per dose / concentration:

4 males / treatment group

Control animals:

no

Positive control reference chemical:

No

Details on dosing and sampling:

Blood samples:
Group 1: 10, 20 ,30, 60 minutes and 2, 4, 8, 16, 24, 48 and 72 hours.
Group 2: 15, 30, 60 minutes and 2, 4, 8, 16, 24, 48, 72 and 96 hours.

Faecal and urine samples:
Group 3: 8, 16, 24, 48, 72 and 96 hours

Tissues samples:
Group 2: Specimens of bone marrow, testes, skin, kidney, lung, duodenum, stomach, spleen, thyroid, thymus, liver, ileum, carcass and fat

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Peak 36Cl concentration in plasma:
10.7 µg/mL at 4 hours after administration (group 1, non-fasted)
7.9 µg/mL at 2 hours following the administration (group 2, fasted)

Absorption rate constant:
0.316/h (group 1)
0.322/h (group 2)

Absorption half-life:
2.2 h (group 1 and 2)
Based on blood kinetics.

Details on distribution in tissues:

36Cl activity % of administration dose / ml at 24 hours following the administration:
Plasma: 1.24 %
The packet cells: 0.29 %
The packet cells (after washing twice with saline) 0.14 %
TCA precipitate: 0.30 %

Subcellular distribution at 24 h after the administration:
75.0 % of total 36Cl activity of the whole liver 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.

Tissue distribution at 96 h after the administration:
Tissue Concentration of 36 Cl (ug/g)
Plasma 1.92
Whole blood 1.59
Bone marrow 1.55
Testes 1.26
Skin 1.20
Kidney 1.13
Lung 1.04
Packed cells 1.03
Duodenum 0.71
Stomach 0.70
Spleen 1.11
Carcass 0.77
Liver 0.74
Ileum 0.59
Fat 0.18

Details on excretion:

Collection period (h) Proportion of HO36Cl excreted (%)
Urine Feces Total
0-8 1.71 ± 1.03
8-16 2.36 ± 0.52
16-24 2.99 ± 0.03
0-24 7.05 ± 1.51 7.45 ± 0.95 14.50 ± 0.56
24-48 12.22 ± 2.12 2.85 ± 0.25 15.00 ± 1.87
48-72 10.02 ± 0.40 1.60 ± 0.30 11.62 ± 0.10
72-96 7.14 ± 1.64 2.90 ± 2.20 10.04 ± 0.56
0-96 36.46 ± 5.67 14.80 ± 3.70 51.23 ± 1.97

Elimination half-life:
88.5 h (group 1)
44.1 h (group 2)

Elimination rate constant:
0.008/h (group 1)
0.016/h (group 2)
Based on blood kinetics.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Metabolism studies revealed that HO36Cl are eliminated as chloride (Cl-), neither ClO2- nor ClO3-.

Any other information on results incl. tables

Read-across justification with data matrices is presented in IUCLID section 13

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
The pharmacokinetic study demonstrated that HO36Cl is readily absorbed into bloodstream after oral administration. The highest 36Cl activity was observed in the plasma and whole blood, while the lowest activity was measured in the liver , ileum and adipose tissue. The substance was converted and eliminated in the chloride form. The excretion was found to be mainly through the urinary route.

Executive summary:

Absorption, distribution, elimination and metabolites of HOCl was investigated in rats. The tissue distribution study revealed the highest 36Cl activity in the plasma and whole blood, while the lowest activity was measured in the liver, ileum and adipose tissue. The plasma carried four times the activity of 36Cl than packed cells. The decrease of total 36Cl after washing packed cells with cold saline suggested that a high percentage of total 36Cl was loosely bound to the erythrocyte membrane or exchangeable with the chloride in saline. Approximately 20 % of the 36Cl in the plasma was bound to protein and in the same time this concentration was higher (five-fold) than the amount which was bound to the liver protein. During the 0 -96 hour time period after administration approximately 51% of the radioactivity was excreted via urine or feces. The main metabolite was identified to be chloride.

This study is considered reliable with restrictions since the study was conducted prior to GLP and internationally accepted test guidelines, but the study is well documented and scientifically acceptable.

The data is used as weight of evidence in the hazard assessment.