Monalazone disodium

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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

Objective of study:

absorption

distribution

excretion

metabolism

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

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

200-300g

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

Dose / conc.:

100 mg/kg bw (total dose)

Remarks:

single oral dose

Dose / conc.:

5 mg/kg bw (total dose)

Remarks:

ip administration on four consecutive days

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.

Type:

absorption

Results:

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

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).

Type:

metabolism

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

Key result

Transfer type:

blood/brain barrier

Observation:

slight transfer

Details on excretion:

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

Metabolites identified:

no

Conclusions:

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

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

significant methodological deficiencies

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

Objective of study:

distribution

excretion

metabolism

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

not specified

Specific details on test material used for the study:

Toluene-4-sulphonamide was supplied by B.D.H. Chemicals Limited, Poole , Dorset, U.K.. No further data.

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 200-250g
- Fasting period before study: no
- Housing: Metabowls (Jencons Scientific Apparatus Limited, Hemd hempstead, Herts., U.K.) for the separate collection of urinc and faeces and allowed free access to food and water before and during the experinwnt.
- Individual metabolism cages: no data
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period:no data

Route of administration:

oral: gavage

Vehicle:

other: In 1.0 ml 20% ethanol in water or 50% aq. propylene glycol (1 ml)

Dose / conc.:

29 mg/kg bw (total dose)

Remarks:

[0.17mmol/kg] containing 8 µCi/rat

Dose / conc.:

200 mg/kg bw (total dose)

Remarks:

[1.17mmol/kg] p-TSA containing 15 µCi/rat

Type:

metabolism

Results:

Metabolites isolated from the 24-hour urine of the low dose group included 4-sulphamoylbenzyl alcohol (3.3 to 4.9% urinary radioactivity) and 4sulphamoylbenzoic acid (93.9 to 95.7% urinary radioactivity), along with unchanged parent compound.

Type:

excretion

Results:

rapidly eliminated from rats, with 78.1% and 63.4% of the radioactivity recovered in the urine within 24 hours in rats dosed with 29 or 200 mg/kg sulfamoylbenzoic acid

Metabolites identified:

yes

Details on metabolites:

Metabolites isolated from the 24-hour urine of the low dose group included 4-sulphamoylbenzyl alcohol (3.3 to 4.9% urinary radioactivity) and 4sulphamoylbenzoic acid (93.9 to 95.7% urinary radioactivity), along with unchanged parent compound. One rat in the low-dose group also produced sulfamoyl-benzaldehyde (1.5% urinary radioactivity). In the high-dose group, 4-sulphamoylbenzoic acid (92.7 to 94.5% urinary radioactivity), 4-sulphamoylbenzyl alcohol (2.0 to 2.7 % urinary radioactivity), and N-acetyl toluene-4-sulfonamide (2.1 to 2.3% urinary radioactivity) were found in the 24-hour urine in addition to the parent compound. The relative amounts of the metabolites suggested that the methyl group of p-TSA is oxidized to produce primarily the benzoic acid derivative. The alcohol and aldehyde, found in trace amounts, represent intermediate steps in metabolism.

Conclusions:

no bioaccumulation potential based on study results.
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.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No toxicokinetics, adsorption, metabolism or distribution is investigated for monalazone disodium.

Based on the 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.