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EC number: 931-295-2
CAS number: -
Accuracy of preparation:
The concentrations analysed in the
formulations of Group 2, Group 3 and Group 4 were in agreement with
target concentrations (i.e. mean accuracies between 85% and 115%).
The slightly higher accuracies may in part
have resulted from the higher nominal concentrations, since nominal
amounts of test substance and vehicle used for formulation were higher
than targeted concentrations. Accuracy was based on target
Small responses at the retention time of the
test substance were observed in the chromatograms of the Group 1
formulations. It was considered to derive from carry over since similar
responses were obtained in the analytical blanks.
The formulations of Group 2 and Group 4 were
homogeneous (i.e. coefficient of variation ≤ 10%).
Analysis of Group 2 and Group 4 formulations
after storage yielded a relative difference of ≤ 10%. Based on this, the
formulations were found to be stable during storage at room temperature
normal laboratory light conditions for at
least 6 hours.
In light of the corrosive properties of the
substance, and the possible local nature of the effects that could
affect a clear evaluation of systemic effects, dosing by dietary route
was recommended for this 90-day study by oral route. However, after
various attempts no adequate analytical method could be developed, and
it was decided to proceed with dose by gavage. Besides, in view of the
low dose levels selected for the study, interference through local
effects that are expected to occur especially in the forestomach (serves
as a storage reservoir in rodents), were considered to be minimal.
Wistar rats were administered 0, 0.5, 2.2 or
8.8 mg/kg bw/d of the test substance by gavage daily for 90 days. The
control group received the vehicle propylene glycol. Examinations were
performed according to OECD 408 with additionally rectal temperature and
estrous cycle determination.
A total of 12/20 animals at 8.8 mg/kg bw/d
were sacrificed in extremis or were found dead between weeks 6 and 10.
Additionally, 2/20 animals at 0.5 mg/kg bw/d and 5/20 animals at 2.2
mg/kg bw/d were sacrificed in extremis in week 12 and between weeks 8
and 12, respectively. All remaining animals at 8.8 mg/kg bw/d were
sacrificed in week 10. Morbidity was related to marked arthritis of the
tarsal joints and/or granuloma(s), with central necrosis of the
mesenteric lymph nodes, and at 8.8 mg/kg bw/d also in one case due to
pleuritis. The incidence and onset of mortality showed an apparent
The hindlegs and/or tail of several rats
treated at 0.5 mg/kg bw/d and the majority of rats treated at 2.2 and
8.8 mg/kg bw/d were affected, showing clinical symptoms such as abnormal
gait/hypotonia/swelling. Occasionally, testicles showed erythema at 8.8
mg/kg bw/d. These clinical signs generally showed an increasing trend
with regard to the number of animals affected and earlier onset of
symptoms with increasing doses. These animals also displayed supportive
macroscopic findings such as thickened hindlegs/tail and/or enlarged
popliteal lymph nodes and/or reduced size of gastrocnemius muscle(s).
Histopathologically, these findings were supported by a dose-related
occurrence of arthritis with or without hyperostosis in the tarsal
joints (up to marked severity at 0.5 mg/kg bw/d and up to massive
severity at 2.2 mg/kg bw/d). In general, lower severities were related
to acute inflammations with edema of the soft tissues surrounding tarsal
bones and joints as hallmark, whereas higher severities were more
frequently noted in chronic inflammations including hyperostosis of
bones and in some cases with fissures of bones. In several animals a
similar histopathology was noted in tail vertebrae (2.2 and 8.8 mg/kg
bw/d) and/or knee joint (8.8 mg/kg bw/d) which in a few cases was
accompanied by atrophy of the gastrocnemius muscle (2.2 and 8.8 mg/kg
bw/d). This atrophy was regarded as a feature of inactivity. All these
findings in the hindlegs can be correlated with in-life clinical
symptoms, such as abnormal gait /hypotonia/swelling. One female treated
at 2.2 mg/kg bw/d showed arthritis of the rib-sternal junction.
The draining popliteal lymph node showed
increased cellularity of the common cell types of lymph nodes (without a
clear predominance) in the cortex and/or medullary cords, similar as
noted in the iliac and renal lymph nodes (supported at necropsy by
enlargement of these nodes). Increased cellularity was also noted for
the liver at 8 mg/kg and correlated to enlargement of the liver.
Granulocytic inflammation (up to marked)
observed in the small intestines (especially in the ileum) at 2.2 mg/kg
bw/d was considered to be due to a direct exposure of the test item or
its metabolite. Furthermore, there were (foamy) macrophages in the
lamina propria up to slight degree noted in most rats at 2.2 mg/kg bw/d.
At 0.5 mg/kg bw/d, there were no test item-related findings in the small
At 0.5 mg/kg bw/d and above, the draining
mesenteric lymph node showed up to massive granulomas with or without
central necrosis (especially at the outer side of the cortex), most
times merging into extranodal inflammation and/or necrosis with or
without peritonitis (up to moderate). Incidences and severity showed a
dose related response. Enlarged mesenteric lymph nodes recorded at
necropsy at 0.5 mg/kg bw/d and above correlated to increased
cellularity, granuloma(s), central necrosis and/or medullary sinus
It was remarkable that there were rats with
granulomas of the mesenteric lymph nodes without a clear relation with
histopathology of the small intestines (granulocytic inflammations).
This started in males at 0.5 mg/kg bw/d with moderate and marked degrees
of granulomas of the mesenteric lymph node without any finding in the
Granulomas were also noted at low incidence
in the spleen at 8.8 mg/kg bw/d (up to marked, only from rats with a
macroscopically enlarged spleen) and liver at 2.2 and 8.8 mg/kg bw/d.
Capsules of these abdominal organs were unaffected (one spleen at 8.8
mg/kg bw/d excluded), making it less plausible that the liver and spleen
findings were caused by peritonitis. The higher spleen weight recorded
for females at 2.2 mg/kg bw/d were attributed to leucocytosis and
granulomas in the spleen.
In the thoracic cavity, major findings were
present in the lung, consisting of adhesions seen at necropsy at 2.2 and
8.8 mg/kg bw/d correlating to inflammation of the pleura (up to marked),
and a clear increase in incidence and severity of perivascular
eosinophilic/lymphocytic infiltrates. Furthermore, there was a slight
increase in severity and/or incidence of alveolar and/or granulomatous
inflammation (correlating to reddish/gray-white foci at necropsy at 0.5
and 2.2 mg/kg bw/d). Secondary changes to the pleural inflammation
consisted in a few cases of serosa infiltrates with inflammatory cells
of thymus or aorta and in one rat (at 8.8 mg/kg bw/d) of watery clear
fluid in the thoracic cavity.
Myeloid hyperplasia of the sternal bone
marrow (up to slight) and leucocytosis (mainly detectable in spleen and
liver, and correlating with the macroscopic finding enlarged) started at
0.5 mg/kg bw/d and are considered to be a consequence of the
inflammatory processes. The neutrophilia recorded for males and females
at 0.5 and 2.2 mg/kg bw/d was regarded to be related to several
inflammatory processes, most severely present in mesenteric lymph nodes
and tarsal joints. Myeloid hyperplasia in the sternal bone marrow could
account for this increase in neutrophils.
Inactive uterus (cervix) epithelium and/or
atrophy/mucification of the vagina epithelium in 1/1 females at 0.5
mg/kg bw/d and 4/10 females at 2.2 mg/kg bw/d, and increased incidence
and/or severity of acinar atrophy in the pancreas and/or sublingual
salivary glands at 2.2 mg/kg bw/d were considered to be related to the
poor health condition, affecting normal estrous cycling behavior.
Summarizing, it remained unclear whether
most findings were caused systemically by direct exposure to the test
item or its metabolite (either by vascular or lymphatic circulation) or
indirectly (e.g. by an elicited immune-mediated response, such as
release of cytokines/chemotaxis from the inflammatory processes in
primarily ileum and/or mesenteric lymph node). Overall, it was
considered that exposure of intestines lead to (necrotizing)
inflammation and granulomas up to massive degrees of draining mesenteric
lymph nodes with possible breakthrough of granulomas into the abdominal
cavity. However, this possibly induced peritonitis cannot explain the
several findings (which are not restricted to surfaces of organs) in
many organs at several locations.
At 2.2 and 8.8 mg/kg bw/d, a lower body
weight/body weight gain and lower food consumption was noted for males
and/or females, essentially during the second half of the treatment
Next to changes in (differential) white
blood cell counts, haematological changes consisted of lower
haemoglobin, haematocrit, mean corpuscular volume and mean corpuscular
haemoglobin, and higher platelet counts in males and/or females at 0.5
and/or 2.2 mg/kg bw/d. Changes in clinical biochemistry parameters
consisted of lower total protein, albumin, cholesterol, glucose and
calcium, and higher chloride in males and/or females at 0.5 and/or 2.2
mg/kg bw/d. Additionally, a higher urinary volume was recorded for both
sexes at 2.2 mg/kg bw/d.
The apparent trend towards a reduction in
grip strength of both fore-and hindlegs across dose groups of both sexes
may be secondary to the observed clinical signs and resulting impairment
of movements. Other functional observation parameters remained
There were no indications of possible
reproductive toxicity based on the parameters determined in this study.
Estrous cycle length/regularity appeared unaffected during the period in
which estrous cycle length was determined (Day 76-91), and
histopathological examination of the male and female reproductive organs
did not show lesions that were directly related to treatment.
No toxicologically relevant changes in
rectal temperature and ophthalmology findings were noted.
Based on these results no NOAEL could be
established and the LOAEL was determined to be 0.5 mg/kg bw/d.
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