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EC number: 696-026-0
CAS number: 1395383-69-3
The oral administration of the test substance to rats by gavage (OECD
408), at dose levels of 10, 100 and 350 mg/kg bw/day, resulted in
findings associated with the irritant nature of the test item at 350 and
100 mg/kg bw/day with histopathological changes in the stomach, duodenum
and kidneys. Therefore based on these results on this study the ‘No
Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was
considered to be 350 mg/kg bw/day for both males and females.
The oral administration of the test substance to rats by gavage, at dose
levels of 10, 100 and 350 mg/kg bw/day, resulted in one premature death
at 350 mg/kg bw/day on Day 53 which was considered to be related to the
administration of the test item, due to the microscopic findings in the
stomach. The premature death of one control female on Day 4 was
considered to be due to trauma during the dosing procedure.
The increased salivation observed in animals treated with 350 or 100
mg/kg bw/day can be attributed to the irritant nature of the test item,
evident from the microscopic findings observed in the stomach. These
clinical observations are therefore considered not to represent systemic
There were no adverse effects on body weight development, food or water
intake for animals of either sex treated with 10, 100 and 350 mg/kg
There were statistically significant reductions in the level of alkaline
phosphatase and cholesterol in males from all dose groups which may be
associated with the increased liver weights. However, there were no
microscopic findings of the liver and therefore these findings were
considered to be of no toxicological significance. The hematological
assessment revealed treated animals showed a reduction in activated
partial thromboplastin time, with 350 mg/kg bw/day males attaining
statistical significance (p<0.05). However, there was no dose
relationship present for animals of either sex and no microscopic
correlates. Therefore, the hematological and blood chemistry assessment
in animals of either sex did not reveal any definitive findings of
toxicological significance and there were no effects on the organ
weights of toxicological importance.
The microscopic changes in the stomach at 350 mg/kg bw/day are likely to
reflect an irritant effect of the test item on the non-glandular mucosa
where there is prolonged exposure due to the unique structure of the
rodent stomach. The hyperplasia and ulceration correlated with necropsy
findings. Whilst this is an adverse change in the animals affected it is
not generally considered to be significant to man as the corresponding
anatomical area is not present.
There were no microscopic changes present in any of the animals treated
with 100 or 10 mg/kg bw/day. Therefore, the macroscopic findings at
necropsy were considered to be of no toxicological significance.
The diffuse tubular hypertrophy noted was a minimal change and
correlates with the necropsy finding of enlarged kidneys and the
statistically significant increase in organ weight. This is considered
likely to be a functional, adaptive change due to increased demand which
may be related to excretion of the test item or metabolites (Frazier K.
S. et al 2012). This was only present in animals treated with 350 mg/kg
The hypertrophy of the mucosa in the duodenum is seen occasionally
related to the administration of some test items (Nolte T. et al 2016).
The significance is unclear however it may be a response to changes in
ingesta (pH for example) or a minor local irritant effect. Given the
lack of any inflammatory or degenerative change it was considered likely
to be adaptive. These microscopic changes were not present in any of the
animals treated with 10 mg/kg bw/day.
Therefore taking into consideration the overall results from this study,
it is considered that a dose level of 350 mg/kg bw/day could be
considered as the No Observed Adverse Effect Level (NOAEL) for systemic
toxicity in both males and females within the confines of this study.
The study was designed to investigate the systemic toxicity of the test
item and is compatible with the following regulatory guidelines:
The OECD Guidelines for Testing of Chemicals No. 408 "Subchronic Oral
Toxicity - Rodent: 90 Day Study” (Adopted 21 September 1998).
The EU Annex B Method B26 - “Subchronic Oral Toxicity Test - Repeated
Dose 90- Day Oral Toxicity Study in Rodents” - updated 21 August 2001.
The United States Environmental Protection Agency (EPA), Health Effects
Test Guidelines, OPPTS 870.3100 - 90 Day Oral Toxicity in Rodents.
This study was also designed to be compatible with Commission Regulation
(EC) No 440/2008 of 30 May 2008, laying down test methods pursuant to
Regulation (EC) No 907/2006 of the European Parliament and of the
Council on the Registration, Evaluation, Authorisation and Restriction
of Chemicals (REACH).
The test item was administered by gavage to three groups, each of ten
male and ten female Wistar Han™:RccHan™:WIST strain rats, for up to
ninety consecutive days, at dose levels of 10, 100 and 350 mg/kg bw/day
A control group of ten males and ten females was dosed with vehicle
alone (Polyethylene glycol 400).
Clinical signs, functional observations, body weight change, dietary
intake and water consumption were monitored during the study. Hematology
and blood chemistry were evaluated for all animals at the end of the
study. Ophthalmoscopic examination was also performed on all animals for
Groups 1 to 4 before treatment and only animals from Groups 1 and 4 were
examined during Week 12 of treatment.
All animals were subjected to gross necropsy examination and
histopathological evaluation of selected tissues was performed.
One control female (No.14) was found dead on Day 4 of treatment
following dosing trauma.
There were no previous clinical signs prior to death or effects on body
weight. Macroscopic examination showed the thoracic cavity was filled
with a clear fluid. The histopathological examination confirmed no
specific changes. Macroscopic post mortem evaluation suggests dosing
trauma may have contributed to the animals death due to finding the
thoracic cavity fluid filled.
One high dose female (no.77) was found dead on Day 53 of treatment. The
clinical signs prior to death included hunched posture, lethargy,
pilo-erection and staining of the snout. The animal had shown actual
body weight loss. Macroscopic post mortem findings included reddened
lungs and reddened jejunum filled with red fluid. The stomach was dark,
distended and filled with red fluid. In addition there was a raised
limiting ridge and sloughing of the glandular region. The microscopic
examination showed general signs of malaise with lymphoid
depletion/atrophy and had notable ulceration in the non-glandular
stomach which is
the likely the cause of death in this case and is considered to be
related to the administration of the test item.
There were no further unscheduled deaths.
There were no clinical observations to indicate systemic toxicity.
There were no treatment-related changes in behavioural parameters
Functional Performance Tests
There were no treatment-related changes in functional performance.
Sensory Reactivity Assessments
There were no treatment-related changes in sensory reactivity.
There was no adverse effect on body weight development in animals of
There was no adverse effect on food consumption or food conversion
The gravimetric measuring of the daily water consumption at the
beginning of treatment for two weeks and two weeks at later stage of the
study showed fluctuations in water intake, without a dose relationship.
Therefore there was no adverse effect on water consumption.
There were no treatment related ocular effects detected.
There were no changes on hematology parameters of toxicological
There were no changes on blood chemical parameters of toxicological
Stomach: At 350 mg/kg bw/day all males showed raised limiting
ridge in the stomach with one male also showing raised white patches on
the non-glandular region of the stomach. The corresponding females also
showed raised limiting ridge with one female also showing thickening
with red patches of the glandular region of the stomach. These
observations correlated with the subsequent histopathological findings.
At 100 mg/kg bw/day two males and two females showed raised limiting
ridge in the stomach.
At 10 mg/kg bw/day one female showed sloughing of the glandular region
of the stomach but with no histopathological correlates.
Kidneys: At 350 mg/kg bw/day four males showed enlarged kidneys;
including one with increased pelvic space and one fluid filled. One
control male and one female treated with 350 mg/kg bw/day also showed
increased pelvic space.
At 350 mg/kg bw/day animals of either sex showed a statistically
significant increase in kidney weights; both absolute and relative to
terminal body weight. Males treated with 100 mg/kg bw/day also showed a
statistically significant increase in kidney weights; both absolute and
relative to terminal body weight. The histopathological findings
correlated with the increased kidney weights at 350 mg/kg bw/day.
Males at 350 mg/kg bw/day also showed a statistically significant
increase in liver weights; both absolute and relative to terminal body
weight. There were no histopathological correlates and therefore this
increase was considered to be of no toxicological significance.
No such effects were noted for females treated with 100 mg/kg bw/day or
animals of either sex at 10 mg/kg bw/day.
The following treatment related microscopic abnormalities were detected:
Hyperplasia of the non-glandular stomach, of minimal or mild severity,
was noted in 8/10 males and all females from the high dose group.
Ulceration of the non-glandular region was noted in one male and
inflammatory cell infiltrate noted in 2/9 females treated with 350 mg/kg
bw/day. This finding was not present in the lower dose groups. These
findings correlated with the necropsy findings.
Hypertrophy of the mucosa of the duodenum, minimal or mild severity, was
noted in 9/10 males and 5/9 females treated with 350 mg/kg bw/day. At
100 mg/kg bw/day this finding was also present in 3/10 males and one
female and not present in animals treated with 10 mg/kg bw/day.
Minimal, diffuse tubular hypertrophy was noted in 8/10 males and 6/9
females treated with 350 mg/kg bw/day. Cortical tubules appeared larger
in diameter with pale staining and sometimes slightly dilated lumen.
These changes correlated with the enlarged kidneys noted at necropsy and
the increased organ weights. These findings were not seen in animals
treated with 10 mg/kg bw/day.
The oral administration of the test substance to rats by gavage, at dose
levels of 10, 100 and 350 mg/kg bw/day, resulted in findings associated
with the irritant nature of the test item at 350 and 100 mg/kg bw/day
with histopathological changes in the stomach, duodenum and kidneys.
Therefore based on these results on this study the ‘No Observed Adverse
Effect Level’ (NOAEL) for systemic toxicity was considered to be 350
mg/kg bw/day for both males and females.
to Annex IX, the extended one-generation reproductive toxicity study
(EOGRTS) is required if the 28- or 90-day study or the screening study
indicates adverse effects on reproductive organs or tissues. In case
there are no triggers for the EOGRTS, a screening study (or a study
providing equivalent information) is enough at Annex IX.
The results of the OECD 408 and OECD 414 did not identify
any adverse effects on reproductive organs or tissues, as a consequence
there is no trigger for the EOGRTs and classification is not required.
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