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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.
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.
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.
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
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
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