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EC number: 275-702-5
CAS number: 71617-10-2
SUBACUTE STUDYThe effects of isopentyl p-methoxycinnamate were examined in a preliminary experiment with 3-week oral application by gavage to Sprague-Dawley rats (5 males and 5 females per group), using daily doses of 0.3, 0.9, and 2.7 mL/kg bw (312, 936, and 2808 mg/kg bw ) in 0.8% hydroxypropyl cellulose gel or the vehicle only at a constant volume of 5 mL/kg bw. The lowest dose of isopentyl p-methoxycinnamate causing observable adverse effects (LOAEL) was estimated within the range of 0.9 mL/kg to 2.7 mL/kg bw/d (corresponding to 936 to 2808 mg/kg/day). SUBCHRONIC STUDYIn this study, groups of 15 male and 15 female Wistar rats each received isopentyl p-methoxycinnamate daily by gavage in dosages of 20, 200, and 2000 mg/kg body weight in polyethylene glycol over a period of 13 weeks. The no observed adverse effect level (NOAEL) for isopentyl p-methoxycinnamate was determined at 200 mg/kg.
"Weight loss" was given as a finding. No direct treatment-related effect
was recognizable, since this finding occured in only a few animals at
isolated times, and one control male was also affected.
Feed and water intakes:
Male and female rats of all dose groups consumed about the same amount
of pelletted feed as the control animals. Drinking-water consumption was
comparable to that of the control group for animals receiving doses up
to and including 200 mg/kg/day. At the dose level of 2,000 mg/kg/day,
drinking-water consumption increased about 13 % in male animals and
about 26% in females.
Body weights: Doses
of up to and including 200 mg/kg/day isopentyl p-methoxycinnamate did
not have any influence on body weight development. At the dose level of
2,000 mg/kg/day, body weights of male rats were lower than those of
following animals died during the study: one control female, one female
of the 20 mg/kg/day dose group, and one male each of the 20 and 200
mg/kg/day dose groups. These deaths were not considered to be related to
Ophthalmological investigations, performed at the beginning and end of
the treatment period, did not reveal any changes related to treatment
with isopentyl p-methoxycinnamate in either the refractory media, the
ocular fundus, or the pupillary reflex.
one month, male rats in the 2,000 mg/kg/day dose group exhibited
slightly lower leukocyte counts, and both males and females had slightly
higher mean corpuscular haemoglobin concentrations than the control
animals. After three months, male rats in the 2000 mg/kg/day dose group
showed a higher haemoglobin content than control animals, as well as a
higher mean haemoglobin content and mean corpuscular haemoglobin
concentration. Female animals revealed higher leukocyte and erythrocyte
counts, a higher haemoglobin content, elevated haematocrit values and
mean corpuscular haemoglobin concentration, and a lower thrombocyte
count. The differential blood count for male rats in the 2,000 mg/kg/day
dose group showed a lower proportion of eosinophils than control animals
after one and three months. In females of this group, the proportion of
segmented neutrophils was higher, and that of lymphocytes was lower than
the control group. Since these differences were only small, however,
they were not considered to be of toxicological relevance.
Clinical chemistry: A
dose of 20 mg/kg/day isopentyl p-methoxycinnamate did not cause any
toxicologically relevant differences from the control animals in the
parameters determined. After one month of treatment, the 200 mg/kg/day
dose resulted in slightly lower cholesterol and higher phosphate
concentrations in male animals, and lower uric acid concentrations in
females, as compared to control animals. After three months, males
exhibited slightly lower creatinine concentrations and females showed a
very slight increase in the Na+-ion concentration. The 2,000
mg/kg/day dose caused the following differences from controls after one
month: higher alkaline-phosphatase activity in male and female animals,
higher GOT activity in females, and higher creatinine, potassium, and
phosphate concentrations in males, lower uric acid and cholesterol
concentrations in males and females, and a reduced calcium concentration
in females. After three months, male and female animals in the 2,000
mg/kg/day dose group exhibited the following changes compared to
controls: higher alkaline phosphatase and GOT activities and Na+-concentration,
lower cholesterol and Ca2+-concentrations. In addition, males
exhibited an elevated bilirubin concentration and lower creatinine
concentration. In females, GPT activity and phosphate concentration were
higher than in control animals. Since the differences in electrolyte
concentrations between treated and control animals were very slight
after one and three months, and no dose-effect-relationship was
recognizable for the drop in creatinine concentration in male animals
after three months, these findings were not considered to be of
Urinalyses: After one
and three months of study, findings of urine investigations of ten rats
per sex and dose did not show any differences between control animals
and treated rats in dose groups up to and including 2,000 mg/kg/day.
Terminal necropsies after three months = None of the necropsies on rats
sacrified after the three-month study indicated treatment-related organ
damage in any of the dose groups.
Organ weights = Organ weights of animals treated with
doses up to and including 200 mg/kg/day did not differ relevantly or
dose-dependently from those of control animals. Male and female animals
in the 2,000-mg/kg dose group exhibited higher absolute and relative
liver weights and relative kidney weights than the corresponding control
animals, and lower absolute and relative spleen weights. Only male
animals showed slightly higher relative heart weights than the controls.
Nearly all animals in the 2,000 mg/kg/day group revealed enlarged
hepatocytes with only lightly stained cytoplasm, mainly in the
peripheral zones of lobules. Some of these cells exhibited enlarged
nuclei. Male and female animals in the 2,000 mg/kg/day group exhibited
an increase in pigment containing iron in the siderocytes of the spleen;
seven of 15 females revealed an increase in pigment containing iron in
Kupffer cells of the liver. Very slight changes (e.g. small retention
cysts in the pars glandularis of the stomach, small vacuoles in cells of
the zona fasciculata of the adrenals, cystic atrophy of the epiphysis)
were seen in some animals of all group and considered to be normal
The effects of repeated oral doses of isopentyl p-methoxycinnamate
administered to rats over a period of 13 weeks were assessed in this
In this study, groups of 15 male and 15 female rats each received
isopentyl p-methoxycinnamate daily by gavage in dosages of 20, 200, and
2,000 mg/kg body weight.
The animals thus treated did not differ in appearance, behaviour,
or mortality from the control animals.
Feed and water intakes were not affected in dose groups up to and
including 200 mg/kg/day. At the dose level of 2,000 mg/kg/day, male and
female animals showed a markedly higher drinking-water consumption than
Doses up to and including 200 mg/kg/day did not have any effect on
body weight development of treated rats. At the dose level of 2,000
mg/kg/day, male rats showed a retardation in body weight development.
Haematological investigations did not provide any indication of a
haemotoxic effect of isopentyl p-methoxycinnamate in dose groups up to
and including 200 mg/kg/day. At the dose level of 2,000 mg/kg/day, an
increase in pigment deposits containing iron in the spleen and liver
indicated an increased breakdown of erythrocytes.
Neither clinico-chemical analyses nor gross-anatomical or
hispathological organ findings indicated any liver damage in dose groups
up to 200 mg/kg/day. At the dose level of 2,000 mg/kg/day, increased
enzyme activities and bilirubin concentrations, and a decreased
concentration of cholesterol in plasma indicated an effect on liver
function. Histopathologically, the condition corresponded to that of a
metabolically activated liver. This was also implied by the higher
absolute and relative liver weights.
Neither the urinalysis or clinico-chemical findings nor the
gross-anatomical or hispathological organ findings indicated any kidney
damage at doses up to 2,000 mg/kg/day.
Necropsies and gross-anatomical investigations of the remaining
organs did not provide any indication of specific organ lesions,
resulting from treatment with isopentyl p-methoxycinnamate in doses up
to and including 2,000 mg/kg/day.
Ophthalmological investigations, conducted before and at the end
of the study on ten male and ten female animals in both the control
group and 2000 mg/kg/day dose group, did not reveal any
treatment-related changes due to isopentyl p-methoxycinnamate.
Thus, under the experimental conditions described, the animals
tolerated doses up to and including 200 mg/kg/day isopentyl
p-methoxycinnamate. Accordingly, the no observed adverse effect level
(NOAEL) for isopentyl p-methoxycinnamate was determined to be 200
In the 3-week subacute oral toxicity study in rats,
the effects of isopentyl p-methoxycinnamate
were examined in Sprague-Dawley rats (5 males and 5 females per group),
using daily doses of 0.3, 0.9, and 2.7 mL/kg bw (312, 936, and 2808
mg/kg bw ) in 0.8% hydroxypropyl cellulose gel or the vehicle only at a
constant volume of 5 mL/kg bw.No
treatment-related adverse effects were observed at the lowest dose. All
animals of the highest dose group appeared slightly haggard and showed
shaggy fur. No remarkable findings in food consumption, behaviour, or
faeces were made in these animals, but the weights of some organs -
spleen, thymus, and gonadal glands in males and spleen and thymus in
females were significantly decreased. The LOAEL of
isopentyl p-methoxycinnamate was estimated to be in the range of 0.9
mL/kg to 2.7 mL/kg/d (936 to 2808 mg/kg/d). Accordingly, the NOAEL would
be 0.3 mL/kg/d (312 mg/kg/d).
In the 13-week subchronic oral toxicity study in
rats, groups of 15 male and 15 female
Wistar rats each received isopentyl p-methoxycinnamate daily by gavage
in dosages of 20, 200, and 2000 mg/kg body weight in polyethylene
glycol. The treated animals did not differ in appearance, behaviour, or
mortality from the control animals. No adverse effects were observed in
the 20 and the 200 mg/kg dose group. Males and females
receiving 2000 mg/kg isopentyl p-methoxycinnamate showed markedly higher
drinking-water consumption and a lower body weight gain than control
animals. At 2000 mg/kg, an increase in pigment deposits containing iron
in the spleen and liver, increased liver enzyme activities and bilirubin
concentrations, and a decreased concentration of cholesterol in plasma
as well as increased absolute and relative liver weights were observed.
No adverse effects on any other organ were observed in this study. The
NOAEL of isopentyl p-methoxycinnamate was determined at 200 mg/kg/day
and the liver was considered the primary target organ.
While the LOAEL and NOAEL obtained in these two
studies are well matching, it remains unclear why the target organs are
not matching, i.e. why no overt effects on the liver were observed in
the 3-week subacute oral toxicity study in rats.
However, it can be concluded from the study results
that oral doses of 312 and 200 mg/kg/day were well tolerated when
administered to rats for 3 and 13 weeks, respectively.
Under the current EU-CLP Regulation, results
obtained from repeated dose toxicity studies are relevant for
classification with respect to specific target organ toxicity - repeated
exposure (STOT-RE). Although a specific target organ for the toxic
action of isopentyl p-methoxycinnamate
was identified in the 13 -week subchronic toxicity study in rats, namely
the liver, the effect observed in this study occurred only at dosages
that do not justify STOT-RE classification of isopentyl
p-methoxycinnamate. According to the current EU-CLP Regulation, overt
effects on specific target organs occurring in oral repeated dose
toxicity studies lasting 28 or 90 days may be considered as relevant for
classification for STOT-RE when they are observed at daily dose levels
of 300 mg/kg/d or below or 100 mg/kg/d or below, respectively. As in the
13-week oral toxicity study in rats, overt effects on the liver were
only observed at the highest dose level of 2000 mg/kg/d, this effect is
not considered relevant for classification. Moreover, the LOAEL obtained
from the 3-week oral toxicity study in rats (936 to 2808 mg/kg/d) also
is well above the 300 mg/kg/d-threshold for STOT-RE that applies for a
28-day study. Accordingly, isopentyl p-methoxycinnamate is not
classified with respect to STOT-RE as specified in the current EU-CLP
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