Monalazone disodium

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of 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:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Monalazone disodium is an organic compound, which has the chemical formula of (C7H4ClNO4S)Na2 and molecular weight 279.60 g/mol. The compound is a solid white powder with a decomposition point at 242ºC °C.
In this document read-across is employed from two source substances (Sodium N-chlorobenzenesulphonamide a.ka. Chloramine B and Tosylchloramide sodium a.k.a. Chloramine T) to a target substance. The target and source substances are mono-constituent substances.
This read-across is based on the hypothesis that the source and target substances have similar physico-chemical, toxicological and environmental fate properties. This prediction is supported by the fact that the substances are structurally similar
The studies conducted on the source substances have been performed according to the current guidelines and in compliance with GLP. The read-across data on the source substances are used as key studies and are considered as valid for the target substance.
Therefore, read-across from toxicokinetic information and the toxicological studies (repeated dose toxicity (oral), study on fertility and reproduction toxicity) on the source substances are considered as an appropriate adaptation to the standard information requirements of Annex VIII of the REACH regulation.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Target substance chemical formula Min% (w/w) Max% (w/w) Typicalconc. % (w/w)
Monalazone disodium (C7H4ClNO4S)Na2 98.0 100.0 99.0
No identified impurities

Source substances
Sodium N-chlorobenzenesulphonamide (C6H6ClNO2S)Na
Tosylchloramide sodium (C7H7SO2NCl)Na


3. ANALOGUE APPROACH JUSTIFICATION
No experimental data on absorption, distribution and excretion is available of the target substance. Based on the target substance structure (ionizable groups), relatively low molecular weight, high water solubility and moderate log Kow values (between-1 and 4) it is expected that monalazone disodium is absorbed readily via GI.

For Chloramine T no bioaccumulation is expected. The substance is rapidly metabolized to the residue marker, p-TSA. p-TSA is rapidly eliminated from rats. The primary metabolite found in the urine is 4-sulfamoylbenzoic acid. The data suggest that the methyl group of p-TSA is oxidized to primarily the benzoic acid derivative.
In conclusion, the read across substance Chloramine T transforms to p-toluenesulfonamide which has no dangerous effects and is secreted from the body. The same mechanism can be assumed for monalazone disodium.
It is very difficult to predict the metabolic changes a substance may undergo on the basis of physico-chemical information alone. Due to the similar structure the metabolites of the target substance are expected to be similar to the source substances.
Thus, the toxicokinetic data on chloramine T and chloramine B is justified in the assessment of the target substance.


4. DATA MATRIX
See APPENDIX of the CSR

Data source

Reference

Reference Type:

publication

Title:

Brain disposition of chloramine-T and neurochemical consequences in rats.

Author:

Anadón A., M.R. Martinez-Larranage, M.L. Fernandez-Cruz, M.E. Morales, M.R. Anton, M.T. Frejo, M.A. Martinez, and M.C.Fernandez

Year:

1997

Bibliographic source:

J Vet Pharmacol Therap 20 (Suppl.1):265-266

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Serial blood collections and brains were taken from Group 1. Tissues were assayed for chloramine-T concentrations. For groups 2 and 3, brains were removed and hypothalamus, striatum, and frontal cortex dissected out. Tissues were analyzed for 5-HT and 5-HIAA. The analysis suggested that chloramine-T is rapidly absorbed and enters the CNS. The ratio of AUCbrain/AUCblood indicated a potential for chloramine-T storage in the brain. Chloramine-T exposure resulted in a decrease in levels of 5-HT in the striatum and frontal cortex (13% and 17%, p<0.05 and p<0.01, respectively). No changes in the levels of 5-HIAA were found.

GLP compliance:

no

Test material

Test material information

1

Reference substance name:

Tosylchloramide sodium

EC Number:

204-854-7

EC Name:

Tosylchloramide sodium

Cas Number:

127-65-1

Molecular formula:

C7H8ClNO2S.Na

IUPAC Name:

Sodium chloro(4-methylbenzene-1-sulfonyl)azanide

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

200-300g

Administration / exposure

Route of administration:

oral: gavage

Details on exposure:

Group 1: 100 mg Chloramine T / kg single oral dose
Group 2: 5 mg Chloramine T / kg ip on four consecutive days
Group 3: 0.5 ml distilled water ip on four consecutive days

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

100 mg/kg bw (total dose)

Remarks:

single oral dose

Doses / concentrations 2

Dose / conc.:

5 mg/kg bw (total dose)

Remarks:

ip administration on four consecutive days

Doses / concentrations 3

Dose / conc.:

0 mg/kg bw (total dose)

Remarks:

0.5ml distilled water ip on four consecutive days

Control animals:

yes

Details on study design:

Group 1 rats (n=8) were killed and serial blood samples were collected and brain removed. Blood and brain samples were assayed for Chloramine T concentration.
Group 2 & 3 rats: brain were removed and hypothalamus, striatum, and frontal cortex were dissected. Hypothalamus, striatum, and frontal cortex were assayd for 5-HT and 5-HIAA concentrations.
Plasma and brain concentrations of Chloramine T were measured by use of HPLC.

Statistics:

Kinetic parameters were obtained by use of an extended least-squares non-linear regression programme.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

The analysis suggested that chloramine-T is rapidly absorbed and enters the CNS.

Main ADME results 2

Type:

distribution

Results:

The ratio of AUCbrain/AUCblood indicated a potential for chloramine-T storage in the brain. Chloramine-T exposure resulted in a decrease in levels of 5-HT in the striatum and frontal cortex (13% and 17%, p<0.05 and p<0.01, respectively).

Main ADME results 3

Type:

metabolism

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral administration 100mg/kg in rats
Rapid absorption. Tmax(Plasma) 0.44h, Tmax(Brain) 0.41h.

Details on distribution in tissues:

Cmax (Plasma) 34.80ug/ml
Cmax (Brain) 52.10ug/ml
AUC brain(plasma) 1.89

Transfer into organs

Key result

Transfer type:

blood/brain barrier

Observation:

slight transfer

Details on excretion:

t1/2 (Plasma) 1.98
t1/2 (Brain) 3.30

Metabolite characterisation studies

Metabolites identified:

no

Applicant's summary and conclusion

Conclusions:

Rapid absorption and a slight accumulation in brain and short elimination time - also from brain.