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EC number: 201-645-2
CAS number: 85-98-3
The value of NOAEL is 50 mg/kg bw/day for males and 150 mg/kg bw/day for females.
The test substance, Centralit ,was tested for subchronic toxicity
using the Method B.26 Sub-Chronic Oral Toxicity Test: Repeated Dose
90-day Oral Toxicity Study in Rodents, Council Regulation (EC) No.
440/2008, Published in O.J. L142, 2008. This sub-chronic oral toxicity
test method is a replicate of theOECD Test Guideline No. 408:Repeated
Dose 90-day Oral Toxicity Studyin Rodents, Adopted 21stSeptember
Wistar rats of SPF quality were used for testing. The test
substance was administered in 0.5% methylcellulose in aqua pro
injectione by stomach tube; oral application of rats was made daily. The
study includes four main groups and two satellite groups of animals.
Each main group consisted of 10 males and 10 females; each satellite
group consisted of 6 males and 6 females.Main groups contained 3 treated
groups of males (doses 50, 150, 600 mg/kg of body weight /day), 3
treated groups of females (doses 50, 150, 450 mg/kg of body weight /day)
and one control group (vehicle only). The satellite groups contained one
control group (vehicle only), one treated group of males (600 mg/kg/day)
and one treated group of females (450 mg/kg/day).
The administration period lasted 90 days. After that animals of
main groups were sacrificed and satellite animals were observed for the
next 28 days without treatment.
Dose levels for the main study for males -
50, 150, 600 mg/kg/day and for females 50, 150, 450 mg/kg/day were
chosen on the basis of results ofstudyCentralit
-Repeated Dose (28 days) Toxicity (Oral), Report No.
12-131, VUOS 2011-2012. The reason for
choice of different high dose levels for males and females was that the
females were found more sensitive to the test substance treatment.
During the 90-day study clinical observation and health status
control were performed daily. The body weight, food consumption were
measured weekly and the detailed clinical observation was carried out in
the same time interval. Water consumption was measured twice and
sequentially three times a week. Ophthalmologic examination was done at
the beginning and at the end of the study. Before the end of study the
functional observation was accomplished. The study was finished by
urinalysis, haematological and biochemical analysis, and gross necropsy
of animals. The selected organs for weighing and histopathological
examination were removed.
During the study the higher
sensitivity to the test substance treatment in females was found out
(two females at the highest dose level and one female at the highest
satellite dose level died after the first application).In
these females distorsion of tail was observed during the pathological
examination. Other pathological findings were not found out.
The effect of the test substance on theheath condition in
femaleswas observed during the 1stweek of study. Negative
effect on neurology system of animals manifested as Straub phenomenon
accompanied by stupor and tachyphoe.
In males no death related to the test substance was recorded. No
effect of the test substance on theheath condition and no effect on
neural system in maleswas observed.
Microscopical exanimations of organs in males showedirreversible,
serious and toxicologically significantnegative effects on kidneys
(early stage of chronic progressive nephropathy) at the highest dose
level. Chronic progressive nephropathy was found out in almost all high
dose males and also in one control males and in three satellite control
males (but only sporadic incidence in control). This finding at kidneys
was accompanied by irreversibly increased weight of kidneys and changes
of biochemical parameters (unbalance of inorganic ions - mainly
decreased value of chloride ions and increased value of sodium ions and
value of inorganic phosphorus). The value of chloride ions was under
historical control limits. The biochemical examination also showed
increased levels of protein and albumin. The value of protein total and
albumin was above historical control limits at the highest dose level
and value of chloride ions was under historical control limits in all
Microscopical exanimations of organs in males showed basophile
pigment in cytoplasm of hepatocytes in liver at the middle and highest
dose levels. The changes in liver were probably adaptive response of
organism to application of the test substance and after finishing of
application these changes either completely disappear or were observed
only sporadically without toxicological significance. This findings in
liver (basophile pigment) was accompanied by reversible increased weight
of liver and changes in some biochemical parameters related to liver
function: decreased activity of ALP, value of bile acids, increased
value of cholinesterase. The value of cholinesterase was above
historical control limits at the highest dose level.
Similarly in females only reversible microscopical change in liver
related to adaptive response organism to the test substance application
was recorded: basophile pigment in cytoplasm of hepatocytes in liver at
the middle and highest dose levels. This finding in liver was
accompanied by others changes: biometry of organs - significantly
increased weight ofliver, haematological parameters – decreased value of
total erythrocyte count and value of haemoglobin, biochemical parameters
– decreased activity of AST and increased value of triglycerides. After
finishing of the test substance application these findingseither
completely disappear or were observed only sporadically without
In both sexes occurred also other changes recorded during
pathological, haematological, biochemical examinations and during
biometry of organs. Occurrence of these findings were rather sporadic
and without toxicological significance.
After consideration of all findings the NOAEL was determined as
The value of NOAEL (No Observed Adverse Effect Level) for
REPEATED DOSE TOXICITY was established 50 mg/kgbody weight/day for MALES
and 150 mg/kgbody weight/day for FEMALES.
value of NOAEL was determined on the base of following findigs in 90
-days repeated dose toxicity study: microscopical examination (early
stage of chronic progressive nepropathy of kidneys in males),
haematological examination (changes of value of total erythrocyte count
and value of haemoglobin in females), biochemical examination (changes
of values of chloride ions, calcium ions, inorganic phosphorus, protein
total, albumin, bile acids, cholinesterase and activity of ALP in males,
changes of value of triglycerides and aktivity of AST in females) and
biometry of organs (changes of weight of kidneys, liver in males and
weight of liver in females).
Justification for selection of repeated dose toxicity via oral
route - systemic effects endpoint:
90-day repeated dose toxicity study caried out base on testing
proposal is available in this endpoint.
Repeated dose toxicity: via oral route - systemic effects (target
organ) urogenital: kidneys
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