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EC number: 204-847-9 | CAS number: 127-52-6
A 28-day oral gavage dose range finding study with Chloramine B was performed in rats at dose levels of 50, 100, 200 and 300 mg/kg bw/day. Based on the results, Chloramine B was then tested in a key 90 -day oral gavage toxicity study at dose levels 20, 60, 180 mg/kg bw/day. The LOAEL was 60 mg/kg bw/day, whereas NOAEL was 20 mg/kg bw/day.
Chloramine B trihydrate was first tested in a supporting 28 -day oral gavage dose range finding study in SPF Wistar rats, at dose levels of 50, 100, 200 and 300 mg/kg bw/day (Valásková, 2007b). No animals died during the study, but clinical effects on health condition (e.g. piloerection, bad condition) were observed at 200 and 300 mg/kg bw/day, and haematology examination showed that the test substance decreased total erythrocyte count, haemoglobin concentration and haematocrit (severally in the dose level 300 mg/kg bw/day). Macroscopic changes were found in skin, stomach and liver at 200 and 300 mg/kg bw/day (markedly pale skin of ears and fingers; changes of stomach mucosa; changes of liver at all levels but not dose related). On the basis of the results, dose levels of 20, 60 and 180 mg/kg bw/day were chosen for the subchronic oral toxicity test.
Chloramine B trihydrate was then tested in a key 90-day oral gavage toxicity study at dose levels 20, 60, 180 mg/kg bw/day (Valásková, 2007a). There was no mortality nor any significant change in functional (behavioural) and ophthalmological observations. The test substance caused reversible decrease in body weight increments in both sexes (more marked in males) in all dose levels. It was connected with reversible decrease of food consumption and food conversion in both sexes. Reversible changes of health status (piloerection) and clinical changes immediately after application (excited behavior) were recorded in both sexes of the highest dose level. Haematological examination showed an effect on leukocyte differential count in both sexes without dependence on dose level. Portion of lymphocytes was increased and portion of monocytes and granulocytes was decreased. In females of the highest dose level also the increase of number of leucocytes and platelets was observed. During biochemical examination of blood the statistically significant changes were detected at the highest dose level: increased value of urea in both sexes, increased value of chloride ions in males, decreased value of AST, creatinine and potassium ions in males, increased value of bilirubin and ALT in females and decreased value of creatinine and sodium ions in females. Increase of bilirubin was irreversible. Statistically significantly decreased volume of urine was detected in males especially at highest dose level. It was connected with increase of specific gravity of urine. Increased value of pH of urine was recorded in satellite males of the dose level 180 mg/kg bw/day and females of the dose levels 60 and 180 mg/kg bw/day. Decreased volume of urine accompanied by higher specific gravity of urine occurred also in females of the dose level 180 mg/kg bw/day. Statistically significant changes in liver and kidney weight at the (middle and) the highest dose in males and females, which were not or only partly reversible after the recovery phase. In males, this was accompanied by change of colour, however only after the dosing phase and not after the recovery phase.
The most important histological affections were diagnosed in kidneys of males of the (mid and) highest dose level –hyaline droplets in renal tubules and mesangial cell proliferation in renal glomeruli. In the same treated group also the increase of incidence of histiocytosis of lymph nodes and involution of thymus was registered. In females the increased incidence of hydrometra (uterus) was found in all treated groups irrespective of dose level. The LOAEL (Lowest Observed Adverse Effect Level) for males and females was established as 60 mg/kg bw/day. The NOAEL (No Observed Adverse Effect Level) for males and females is 20 mg/kg bw/day.
Potential target organs for the 90-day oral gavage toxicity study were assessed as follows:
- Statistically significant increases in liver weights (not reversible) and change of colour (reversible) were observed at (mid and) high dose levels in male and female rats, however without associated histological findings. In addition, females of the highest dose level showed an irreversible increase in serum bilirubin. Therefore, liver was considered to be a target organ.
- Histological findings in the kidney were only seen in males: hyaline droplets in renal tubules (60 & 180 mg/kg) and mesangial cell proliferation in renal glomeruli (180 mg/kg). Hyaline droplets have been described as alpha-2-microglobulins, which is the major urinary fraction in male rats. A wide range of compounds is reported to enhance the development of hyaline droplets without relevance for humans (Greaves P.; Histopathology of preclinical toxicity studies, Urinary tract, 2008). Proliferative lesions associated with the renal corpuscle involve Bowman´s capsule, the mesangium and the juxtaglomerular body. None of these lesions has been associated with neoplasia in the rat. (Hard, G.C., Alden, C.L., Stula, E.F., Trump, B.F., 1995,Proliferative Lesions of the Kidney in Rats, In: Guides for Toxicologic Pathology, STP/ARP/AFIP, Washington, DC). Only the mesangial cell proliferation at the highest dose group is retained as relevant effect for target organs.
- Histiocytosis was seen in the lymph nodes in males dosed at 180 mg/kg. Histiocytosis is characterised by presence of large macrophages, and may be related to administration of compounds or commonly seen in ageing rats (Greaves P.; Histopathology of preclinical toxicity studies, Haematopoietic and Lymphatic systems, 2008). As the effect was only seen in males, and not any more after the recovery period, this is not considered to be a target organ.
- Thymus atrophy was seen in male rats dosed at 180 mg/kg. Involution is a common finding in rats and other species (Greaves P.; Histopathology of preclinical toxicity studies, Urinary tract, 2008). As there was no statistically significant decrease in thymus weights after dosing and recovery period, this is not considered to be a target organ.
- Uterus hydrometra was observed in female rats at various dosed groups. Cyclical endometrial changes are related to glandular and stromal proliferation during prooestrus and oestrus, followed by a secretory phase during dioestrus. Although the endometrium shows the most dramatic changes during the oestrus or menstrual cycle, overall uterine size and weight also increase during the oestrus cycle. In rodents, some of these cyclical changes are the result of uterine dilatation and accumulation of uterine fluid but the myometrium also increases thickness (Greaves P.; Histopathology of preclinical toxicity studies, Female genital tract, 2008). Therefore the findings were rather considered to be due to normal variation.
- In conclusion, liver and kidney were retained as target organs due to relevant changes at the highest dose level of 180 mg/kg bw. The other changes at the same dose level and changes at 60 mg/kg were not considered adverse or significant, therefore no changes need to be classified.
Supporting studies were further available with Chloramine T or its metabolite p-TSA (and related product o-TSA). From these studies, it was clear that same target organs (liver and kidney) were observed and that NOAEL values were in the same range, i.e. 100 -150 mg/kg bw for the subacute and 15 -50 mg/kg for the subchronic toxicity studies in rats:
- Rats were exposed to Chloramine T for 28 days in the diet at 150, 500 and 1500 mg/kg bw/day. The mid- and high-dose groups demonstrated a significant decreased weight gain, slightly increased leukocyte count, and pale discoloration of the liver. Increased relative kidney and liver weight were observed in all dose groups. There were no significant treatment-related histologic alterations. NOAEL was 150 mg/kg bw.
- Rats were exposed to Chloramine T for 90 days in the diet at 5, 15, 50 and 150 mg/kg bw/day. The highest dose resulted in a slight reduction in weight gain in females. Increased relative kidney weights were observed in the top 2 dose groups in both sexes. Relative liver weights were increased in all of the dose groups. Increased severity and frequency of calcareous deposits were observed in the kidneys of the 50 and 150 mg/kg bw/day groups for females only. A NOEL of approximately 15 mg/kg bw was established.
- Rats were exposed to p- and o-TSA for 90 days in the diet at 5, 15, 50 and 150 mg/kg bw/day. The only treatment-related effect was a slight reduction in food consumption and weight gain at the high dose. NOAEL was 50 mg/kg bw.
- Dogs were exposed to p- and o-TSA for 90 days at 75 mg/kg bw/day. No treatment-related effects were observed. No hematologic or histopathologic analyses were performed for animals in the mid and high dose treatment groups, so no NOEL was derived.
Beagle dogs were dosed orally or intravenously, or through a combination of the two, with doses ranging from approximately 12.8 to 640 mg/kg per day for up to six months. In the study, 50% of the animals were sacrificed at 17 weeks. At that time, persistent mild or moderate anemia was observed. A reduction in Elastase Inhibitory Concentration (EIC) was found in the serum from the dosed animals. Furthermore, a reduction in EIC was found in the pulmonary lavage fluid. However the levels of immunologically determined protease inhibitor did not change with treatment, therefore, the enzyme must have been inactivated by chloramine T. The reaction was specific for the protease inhibitor, as the ability to inhibit trypsin was less affected. Emphysema-like alterations in lung morphology were found in both studies. The data suggest that this model parallels the emphysema associated with the genetic a-l-proteinase inhibitor deficiency in man. The intravenous study part is not considered relevant for the repeated dose toxicity, as the administration route is not relevant for man.
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.
There were no inhalation and dermal toxicity studies. Both subacute and subchronic testing were waived based on scientific reasons.
No acute inhalation toxicity data or studies directly for Chloramine B (Sodium N-chlorobenzenesulphonamide trihydrate) are available. Chloramine B trihydrate has a very low 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 ). Further, particle size distribution in the tested sample of Chloramine B shows that only 1 % of particles are less than 100 μm in diameter, thus Chloramine B practically cannot penetrate in the alveolar region of the lungs.
More information is provided in a waiver documentation, attached to Section 13.
Dermal route was not considered relevant based on absence of effects and penetration as demonstrated in acute dermal toxicity and in vitro dermal absorption studies.
No significant effects were noted under treshold levels for repeated dose toxicity, therefore Chloramine B trihydrate does not need to be classified for repeated dose toxicity according to the Directive 67/548/EEC, Annex VI and CLP regulation (No. 1272/2008 of 16 December 2008).
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