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Description of key information

No studies of toxicokinetics, metabolism or distribution in organism were available for Chloramine B trihydrate, except for an in vitro study for dermal absorption. In this study, Chloramine B was not detected in any of the analysed fractions and receptor fluid, only a minimal fraction of its degradation product Benzenesulfonamide were detected in the skin fractions and receptor fluid (1 and 8%, respectively after 6 & 24h). Failure of dermal absorption was confirmed in a percutaneous absorption study of read across substance Chloramine T on cow  teats as udder disinfection. For risk characterisation, 10% dermal absorption is considered from a conservative viewpoint. 
Further studies with Chloramine T (Tosylchloramide sodium) in rats demonstrated a rapid distribution and elimination phase and high plasma clearance. After 96 h, 36% was eliminated via the urine, whereas 15% was eliminated via faeces, however further metabolites were assumed, as described here below. When p-Toluenesulfonic acid (p-TSA, the same substance without N-group) was given in rats, it was rapidly eliminated in the urine within 24h and metabolites isolated included mainly 4- sulphamoylbenzoic acid (93.9 to 95.7%) and further 4-sulphamoylbenzyl alcohol and N-acetyl toluene-4-sulfonamide along with unchanged parent compound.
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 Chloramine B trihydrate which transforms in the body to benzenesulfonamide.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
5

Additional information

No studies of toxicokinetics, metabolism or distribution in organism were available for Chloramine B trihydrate, however the substance disintegrates to Benzenesulfonamide during application. Substance Benzensulfonamide contains a sulfo-group, which generally reduces toxicity of structurally similar substances, and both are readily soluble, which should facilitate their elimination from organism. The read across substance Chloramine T (Tosylchloramide sodium) transforms to p-Toluenesulfonamide which, according to tests, has no dangerous effects and is secreted from the body. Following weight of evidence is provided.

Toxicokinetics, metabolism and elimination for Chloramine T (Tosylchloramide) and p-TSA (p-Toluenesulfonic acid):

a. In Wistar rats, toxicokinetics of Chloramine-T after single 30 mg/kg i.v. and 100 mg/kg p.o. was characterized by a rapid distribution and elimination phase (distribution half-life 0.12 hr -i.v. and 0.42 hr -p.o.; elimination half-life 1.41 hr -i.v. and 1.98 hr -p.o). Plasma clearance was relatively high (0.147 L/hr - i.v., 0.149 L/hr- p.o.) with a volume distribution at steady state of 0.24 L. Chloramine-T was found to be rapidly distributed and eliminated. After 96 h, 36% was eliminated via the urine, whereas 15% was eliminated via faeces, however further metabolites were assumed, as described here below.

b. Administered p-TSA given in rats was rapidly eliminated from rats, with 78.1% and 63.4% of the radioactivity recovered in the urine within 24h in rats dosed with 29 or 200mg/kg (Ball et al, 1978). Metabolites isolated from the 24-hour urine of the low dose group included 4-sulfamoylbenzyl alcohol (3.3 to 4.9% urinary radioactivity) and 4- sulfamoylbenzoic 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. It was found that 80% of administered p-TSA was found in the urine; 50% of that had been metabolized to 4-sulphamoylbenzoic acid (Ball et al, 1978).

A read-across justification was worked out and separately attached in Section 13. Based on the data from the repeated dose toxicity studies, as well as the comparable molecular structure and similar physicochemical properties, it was concluded that both data from Chloramine B trihydrate as those of Chloramine T and metabolites such as BSA and p- and o-TSA can be used for read-across.

Dermal absorption:

a. A key study for skin absorption was performed with Chloramine B trihydrate on full-thickness porcine skin according to OECD TG 428 method (Bendova & Rucki, 2010). Disc-shaped pieces, (diameter 5cm) were defrozen prior to testing (2-3 hours). Metabolic status was metabolically non-active. 40 µl was applied for different durations (1h, 2h, 4h, 6h, 8h and 24h). At the end of exposure the skin surface was wiped using a metal spatula (fraction 1), the skin preparation was then cut into small pieces (fraction 2) and the receptor fluid was collected (fraction 3). After application on skin, Chloramine B was not detected in any of the analysed fractions and receptor fluid, it is not absorbed in the skin and does not penetrate. Only the presence of its degradation product, Benzenesulfonamide, was detected in the skin fractions and receptor fluid: after short-term exposure its penetration is negligible (1% after 6h), after 24 h exposure its penetration is low (8%).The maximum dose of Benzenesulfonamide, which would penetrate the organism after 6 hours - 0.15 mg/kg/day, is many times lower than the NOAEL value determined in a 90-day subchronical oral study (20 mg/kg bw/day). At the specified normal way of usage, Chloramine B shall not penetrate the organism and the effects of its metabolite Benzenesulfonamide may be considered negligible.

b. A supporting in vivo study with percutaneous absorption of Tosylchloramide sodium was available for bovine application. There was interest in using Tosylchloramide sodium as a teat and udder disinfection to prevent udder disease in lactating cows. Two studies were identified investigating the potential for absorption of the parent compound or the excretion of p-TSA in the milk. Analysis of blood samples failed to detect either Tosylchloramide sodium or p-TSA. Small amounts of p-TSA (5 - 9 µg/kg milk) were found in about one-third of the individual milk samples. Sampling from the bulk tank failed to detect any p-TSA. These studies suggest the percutaneous absorption and transfer of Tosylchloramide sodium to the blood stream was negligible.

Respiratory absorption:

Respiratory absorption of Chloramine B trihydrate either as powder or as aerosol was assessed based on specific physicochemical data and based on particle size measurements from aerosol products. Further details on source(s) and interpretation can be found in attachment.

- Chloramine B trihydrate has a vapour pressure ranging between 1536 Pa (20°C) and 1976 Pa (25°C),whereas Chloramine B showed a very low vapour pressure value (2.44 x 10-9Pa ). There may be (in worst case) some co-evaporation of Chloramine B trihydrate and water (2340 Pa at 20°C), however this is very limited in time. After a while, evaporation rate of Chloramine B will account, which is below the threshold for inhalation testing. As a general guide, highly volatile substances are those with a vapour pressure greater than 25 KPa (or a boiling point below 50°C). Based on these considerations, deposition and absorption of Chloramine B trihydrate in the respiratory tract is considered to be very low.

- Chloramine B trihydrate has a high particle size; less than 1% of particles are in the range of < 100µm, therefore they are not able to enter they higher and lower respiratory airways.

- Chloramine B trihydrate has a high water solubility (221 g/L), which is in the same range as Chloramine B (292 g/L). As a general rule, highly water soluble substances will be deposited in the mucus of the respiratory epithelium, by which penetration in the lower respiratory tract (where absorption takes places) is less likely. 

- On the other hand, Chloramine B trihydrate has a logPow of 0.14, which is in the same range as Chloramine B (-1.05 or 0.29, calculated or from database). As a general rule, moderate log P values (between -1 and 4) are favorable for absorption directly across the respiratory tract epithelium by passive diffusion. However as the substance, if present in inhaled air, is deposited on and in the mucus layer, no further absorption is considered to take place.

- When aerosol generation was taken into account, droplet size distribution for trigger disinfectant sprays used by consumers was demonstrated to be above the respirable size of particles that can enter the alveolar region of the lungs. For professional use where (low and) high pressure may be used, exposure is excluded by the obligation to wear appropriate PPE. Therefore there is no hazard for inhalation absorption.

- In conclusion, the inhalation route is not considered to be relevant for exposure to Chloramine B trihydrate, either as a powder or an aerosol. Therefore acute and repeated dose inhalation testing was waived, whereas the oral route was considered as the most appropriate testing route for systemic toxicity.