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EC number: 701-122-3
CAS number: 106185-75-5
NOAEL for males and females (OECD guideline 408): 891 mg/kg bw/day and 1109 mg/kg bw/day, respectively.
was confirmed for the test substance in Rat and Mouse No. 1 maintenance
diet formulations at nominal concentrations of 100 ppm and 24000 ppm. Stability
was confirmed at ambient storage for up to one day and frozen storage
for 16 days for 100 ppm, at ambient storage for up to one day and frozen
storage for 22 days for 500 ppm and at ambient storage for up to 8 days
and frozen storage for 22 days for 24000 ppm.
mean concentrations of the test substance in test formulations analysed
for the study was within +10 %/-15 % of nominal concentrations,
confirming accurate formulation. The percent difference from mean
remained within 3 % confirming the precision of the analysis.
a repeated dose toxicity study performed in accordance with OECD test
guideline No. 408 and in compliance with GLP, test substance 2-ETHYL-4
-(2,2,3- TRIMETHYLCYCLOPENT- 3-EN-1-YL) BUT-(2E)-EN-1-OL was
administered orally via the diet to groups of Crl:CD(SD) rats
(10/sex/dose) at doses of 1500, 5000 or 15000 ppm for 13 weeks. A
similarly constituted Control group received untreated diet, with
vehicle (corn oil) only, throughout the treatment period. A further five
male and five female rats were assigned to each of the control and high
dose groups. These animals were treated for 13 weeks, followed by a four
week period without treatment to assess the potential for any
treatment-related change to recover. During the study, assessment of
clinical condition, detailed physical and arena observations, sensory
reactivity, grip strength, motor activity, body weight, food
consumption, water consumption (visual observations), ophthalmoscopy,
haematology, coagulation, blood chemistry,
weights, macropathology and histopathology investigations were
overall achieved doses during Weeks 1-13 at 1500, 5000 and 15000 ppm
were 100, 330 and 981 mg/kg bw/day for males and 109, 362 and 1109 mg/kg
bw/day for females, respectively.
were no premature deaths and no test article-related signs observed
during the detailed physical examination and arena observations.
reactivity observations, grip strength, motor activity scores and
ophthalmoscopy assessments for all groups of animals during Week 12 were
unaffected by treatment.
body weight gain of males and females given 15000 ppm was generally
lower than Control throughout the treatment period (64% and 61% of
Controls for males and females, respectively), with the most pronounced
effects occurring in Week 1. Males given 5000 ppm showed statistically
significant low mean body weight gain during Weeks 1-2 of treatment but
thereafter were essentially similar to Control. Following the
replacement of treated diet by untreated diet (with vehicle), the mean
body weight gain of males and females previously given 15000 ppm was
statistically significantly higher than Control (at least 200% of
Control) over the 4-week recovery period. The mean body weight gain of
females given 5000 ppm and of males and females given 1500 ppm was
unaffected by treatment.
mean food intake of animals given 15000 ppm was markedly lower than
Control in Week 1 of treatment; thereafter, a clear increase in food
consumption was apparent although weekly food intake remained lower than
Control throughout the treatment period (overall food intake was 68 %
and 73 % of Control for males and females, respectively). After
replacement of the treated diet by untreated diet (with vehicle),
animals in the 15000 ppm group showed a marked increase in food
food consumption, with associated reductions in body weight gain was
thus evident in the 15000 ppm group, however this was deemed
attributable to the treated diet being slightly unpalatable due to the
class and high concentration of the test article, but not adverse as
there was no evidence of primary toxicity.
of haematological parameters during Week 13 of treatment revealed lower
than Control erythrocyte and haemoglobin concentrations and haematocrit
in males and females given 15000 ppm, associated with a minor increase
in red cell distribution width, and a slight decrease in mean cell
haemoglobin concentration in females. All
groups of treated males showed shorter than Control prothrombin times,
with some evidence of a dose-related trend. Conversely,
all groups of treated females showed shorter than Control activated
partial thromboplastin times. All
these differences were within 95 % confidence limits of the Historical
Control Data range and were no longer evident 4 weeks after the
cessation of dosing.
Week 13, biochemical analysis of plasma revealed a non-dose-dependent
decrease in urea, blood urea nitrogen and creatinine concentrations in
all groups of treated males and females when compared to Controls. In
addition, cholesterol concentrations were slightly high in males and
females given 15000 ppm, changes in glucose concentrations were apparent
in 15000 ppm group (slightly low in males and slightly high in females),
alkaline phosphatase, albumin concentrations and albumin/globulin ratio
were slightly high in males given 15000 ppm and aspartate
amino-transferase concentrations were slightly low in females given
15000 ppm. All
these differences were within 95% confidence limits of the Historical
Control Data range and were no longer evident after 4 weeks off-dose.
analysis of organ weights following 13 weeks of treatment indicated
dose-dependent and statistically significantly higher than Control body
weight-adjusted liver weight in all groups of treated males and in
females given 5000 or 15000 ppm. Body weight-adjusted kidney weights
were higher than Control in females given 15000 ppm, and body
weight-adjusted uterus and cervix weights were slightly low in females
given 5000 or 15000 ppm. Following 4 weeks of recovery, body
weight-adjusted liver weights in males previously given 15000 ppm
remained slightly higher than Control, although the magnitude of the
difference was lower than that recorded at the end of the treatment
period. In females previously given 15000 ppm, body weight-adjusted
kidney weights remained higher than Control.
biochemistry revealed several slight changes in composition which were
indicative of adaptations of metabolism/excretion in the liver and
kidneys, and were accompanied by increases in liver and kidney weight.
In the absence of any evidence of degenerative or functional change in
the liver and kidneys during histopathological evaluation, the slight
disturbances of biochemical parameters were considered not to be
were no macroscopic abnormalities detected at scheduled termination
after 13 weeks of treatment or after 4 weeks of recovery that were
attributable to treatment.
evaluation of the retained tissues revealed limited changes in the
adrenal glands and thymus. Non-adverse
diffuse hypertrophy of
the zona glomerulosa in the adrenal glands was seen in females given
5000 or 15000 ppm, and in one male given 15000 ppm. Full recovery was
apparent after the four week recovery period. In addition, a minimal to
slight increase in the incidence of tingible body macrophages was seen
in the thymic cortex of animals in all treated groups. This change was
considered to be secondary and stress-related and was no longer apparent
after the 4-week recovery period.
was concluded that dietary administration of the test item to Crl:CD(SD)
rats at dietary inclusion levels of 1500, 5000 or 15000 ppm for 13 weeks
provied clearevidence of systemic exposure but no effects which were
deeme to be adverse.
In an oral repeated dose toxicity
range-finding experiment, male and female rats exposed for 14 days
showed increased liver weight in both sexes and a slight increase in
kidney weight in females.
Also, in a 13-week repeated dose toxicity
study conducted according to GLP and OECD guideline 408, males and/or
females exposed by diet to the registered substance showed slight
non-adverse and reversible changes in haematological parameters
(erythrocyte and haemoglobin concentrations, prothrombin time and
haematocrit), biochemical parameters (urea,
blood urea nitrogen and creatinine concentrations, glucose,alkaline
phosphatase, albumin concentrations and albumin/globulin ratio),
associated with increases in liver and/or kidney weights. These
observations are thought to be indicative of adaptations of
metabolism/excretion in the liver and kidneys, with absence of
degenerative or functional change in liver or kidneys. Therefore,
the NOAEL was concluded to be 15000 ppm, equivalent to 981 mg/kg bw/day
for males and 1109 mg/kg bw/day for females.
No adverse effects were observed below the
limit of classification of 300 mg/kg bw/day for subacute studies or 100
mg/kg bw/day for subchronic studies, therefore the registered substance
is not classified for repeated dose toxicity according to Directive
67/548/EEC and CLP Regulation (EC) n° 1272/2008.
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