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EC number: 275-702-5
CAS number: 71617-10-2
A short description of the key studies is provided at the beginning of the Discussion section.
The potential reproductive toxicity of 2-ethylhexyl
4-methoxycinnamate, a compound that is structurally similar
p-methoxycinnamate, was investigated in a two-generation
reproductive toxicity study in rats.
this study, wistar rats (25 animals per sex and dose group) continuously
received the test compound in the diet through two successive
generations at nominal doses of 150, 450, or 1,000 mg/kg bw/d. OMC had
no adverse effects on oestrous cycles, mating behaviour, conception,
parturition, lactation and weaning, sperm and follicle parameters,
macropathology, and histopathology of the sexual organs.
mg/kg bw/d reduced parental food consumption and body weight (-14% to
-16% in males, -4% to -5% females), increased liver weight, produced
hepatic cytoplasmic eosinophilia and erosion/ulceration of glandular
stomach mucosa, and led to a slightly decreased implantation rate in the
top dose F0 and F1 dams. The high dose F1 and F2 pups had reduced
lactation weight gain and organ weights and delayed sexual maturation
landmarks. There was no evidence of a selective influence of the test
compound on pups' sexual landmarks.
NOAEL (no observed adverse effect level) is 450 mg/kg bw/d for fertility
and reproductive performance, for systemic parental and developmental
to the high degree of structural similarity between isopentyl
the negative findings obtained with 2-ethylhexyl
in this study suggest that isopentyl
would also not show any reproductive or developmental toxicity.
the two-generation reproduction toxicity study conducted with 2-ethylhexyl
4-methoxycinnamate, Wistar rats
continuously received the test compound in the diet through two
successive generations at nominal doses of 0, 150, 450 or 1000 mg/kg
bw/day (Schneider et al. 2005; see
also section 7.8.1 of this IUCLID dataset).
The study was performed according to OECD guideline no. 416.
the highest dose level, reductions in food consumption and body weight,
increases in liver weight, hepatic cytoplasmic eosinophilia and
erosion/ulceration of glandular stomach mucosa were observed in the
parental animals. A slightly decreased implantation rate was also
observed in the top dose F0 and F1 females, although the implantation
rate was within or close to the historical control range. A slightly
decreased implantation rate at the highest dose, at which parental
animals show signs of toxicity, is not unusual and was considered most
likely to be secondary to the maternal toxicity observed. High dose F1
and F2 pups had reduced lactation weight gain and organ weights and
delayed sexual maturation landmarks. There was no evidence of a
selective influence of the test compound on pups sexual landmarks. Rather,
the delay in sexual maturation was considered to be secondary to the
reduced pup weight gain, since body weights at time of sexual maturity
were similar between controls and treated pups. Body weight rather than
calendar age is the main factor driving sexual maturity.
NOAEL of 2-ethylhexyl
4-methoxycinnamate by continuous
dietary administration was thus determined to be 450 mg/kg bw/day for
fertility and reproduction parameters, for systemic parental and
developmental toxicity. This is based on reduced body weights, increased
liver weight and hepatic cytoplasmic eosinophilia in the parents, a
secondary reduction in implantation rate, and
reduced body weights and delayed sexual
maturation of the pups at 1000 mg/kg bw/day.
Short description of key information:
The effects of isopentyl p-methoxycinnamate on fertility were not
However, information on this endpoint is available from a two-generation
reproduction toxicity in rats which was performed with 2-ethylhexyl
4-methoxycinnamate, a compound that is structurally similar to isopentyl
p-methoxycinnamate (Schneider et al. 2005; see also section 7.8.1 of
this IUCLID dataset and the section "discussion" below for further
In addition, in an oral subchronic 90-day study performed with isopentyl
p-methoxycinnamate in the rat, histopathological examination did not
reveal any significant effects on reproductive organs upon oral dosing
at up to 2,000 mg/kg bw/day (see section 7.5.1 of this IUCLID dataset).
Justification for selection of Effect on fertility via oral route:
Read-across study with 2-ethylhexyl 4-methoxycinnamate
The embryotoxic and/or teratogenic potential of isopentyl p-methoxycinnamate was evaluated in Wistar rats (Study no. 1988034). The study was conducted in accordance with OECD guideline no. 414. Mated females (n=20 per dose) received daily oral doses of 0.25, 0.75, and 2.25 mL/kg/d isopentyl p-methoxycinnamate in olive oil or the vehicle only from day 6 post coitum up to and including day 15 post coitum. Tretinoin was used as a positive control. The animals were sacrificed at day 20 post coitum and subjected to necropsy.No teratogenic effects were observed at any of the dose levels tested. Embryotoxicity was observed at the highest dose level (2.25 mg/kg/d). However, this effect was considered to be a consequence of the high degree of maternal toxicity that was observed at this dose level and was not considered to be due to a specific embryotoxic action of the test item. Accordingly, it can be concluded that no teratogenic or specifically embryotoxic effects of isopentyl p-methoxycinnamate were observed in this study.When strict criteria of general maternal toxicity were applied, the no observed adverse effect level (NOAEL) for maternal toxicity was determined at 0.25 mL/kg/d. However, as the only relevant adverse effect that was observed at the intermediate dose level of 0.75 mL/kg/d was hair loss, which may be considered a minor adverse effect, the intermediate dose level of 0.75 mL/kg/d might be considered as NOAEL in this case.
female Wistar rats were treated with daily oral doses of 0.25, 0.75, and
2.25 mL/kg/d isopentyl
p-methoxycinnamate from day 6 post
coitum to day 15 post coitum. No teratogenic effects were observed at
any of the dose levels tested. Embryotoxicity observed at the highest
dose level (2.25 mg/kg/d) were attributed to the high degree of maternal
toxicity that was observed at this dose level and was not considered to
be a consequence of a specific embryotoxic effect of the test item.
Accordingly, no teratogenic or specific embryotoxic effects of isopentyl
p-methoxycinnamate were observed in
hair loss was the only relevant toxic effect observed in mothers at 0.75
mL/kg/d, this intermediate dose level may be considered as the NOAEL.
Justification for selection of Effect on developmental
toxicity: via oral route:
ASSAY IN IMMATURE FEMALE RATS (IN VIVO) (STUDY NO. 2001155)
this assay, juvenile female Wistar rats (n=6 per dose level) received
daily subcutaneous injections of isopentyl p-methoxycinnamate (200 or
1000 mg/kg in corn oil) for 3 consecutive days. Two positive control
groups of 6 juvenile female rats each were treated daily for 3
consecutive days with 0.3 or 1.0 µg/kg 17alpha-ethinyloestradiol, two
further groups of 6 juvenile female rats received the vehicle alone or
were left untreated. The study was performed in accordance with the OECD
Draft protocol B - Immature female rats with subcutaneous
administration. No effects on uterine weight were observed at 200 and
1000 mg/kg isopentyl p-methoxycinnamate. An enlargement of uterus and
increased uterine weights were observed with the positive control. In
conclusion, the test item did not show any estrogenic effects in this
RECEPTOR BINDING ASSAY (IN VITRO) (STUDY NO. 2002031)
the in vitro androgen receptor binding assay, the potential
interaction of the test item with the androgen receptor was investigated
using a rat recombinant fusion protein containing both the hinge region
and ligand binding domain of the androgen receptor and radiolabelled
methyltrienolone as ligand.
p-methoxycinnamate only weakly displaced methyltrienolone from the
androgen receptor (25% and 35%, respectively, at 100 µM in two
independent experiments) and no IC50 value could be established. These
results did not suggest a specific interaction of the test item with the
RECEPTOR BINDING ASSAY (IN VITRO) (STUDY NO. 2002077)
this assay, the potential interaction of the test item with the estrogen
receptor was investigated using a human recombinant estrogen receptor of
the alpha-subtype and radiolabelled estradiol as ligand. In this assay,
the test item did not show any affinity to the estrogen receptor at
concentrations ranging from 0.1 to 100 µM.
TRANSCRIPTIONAL ACTIVATION ASSAY (IN VITRO) (Kunz et al. 2006)
this published study, Kunz et al. (2006) investigated thein vitro oestrogenic
activity of isopentyl p-methoxycinnamate in two yeast transactivational
assays. A recombinant yeast was employed, which was stably transfected
with either the oestrogen receptor alpha of rainbow trout or the human
oestrogen receptor alpha. The test item did not result in any
transactivational effects with either oestrogen receptor, indicating
that it does not have any agonistic estrogenic activity in either of
these two assay systems at concentrations ranging from 10-9 to
TRANSCRIPTIONAL ACTIVATION ASSAY (IN VITRO) (Kunz and Fent 2006)
In this published study, Kunz and Fent
(2006) systematically investigated the in vitro (anti-)oestrogenic
and (anti-)androgenic activity of isopentyl p-methoxycinnamate in a
transactivational assay. The recombinant yeast (S. cerevisiae)
was employed, which was stably transfected with either the hERa or the
human androgen receptor (hAR). The tested concentration range was 10-7to
10-2M. No oestrogenic transactivation was measureable in the
oestrogen agonism assay. However, multiple hormonal activity was
observed, with effects in the anti-oestrogenic, androgenic and
anti-androgenic assays. Complete inhibition of E2-induced activity was
measured at the highest concentration tested and a full dose-response
curve was obtained. The IC50 was determined as 297 µM, which represented
a potency 540 times lower than the known anti-oestrogen
4-hydroxytamoxifen. Isopentyl p-methoxycinnamate displayed partial
agonistic activity in the androgen assay, indicated by a sub-maximal
dose-response curve (curve height was 52% that of DHT). The EC50 was
determined as 429 µM, representing a potency 260,000 times lower than
the natural ligand DHT. A full dose-response curve with complete
inhibition of DHT was observed in the anti-androgenic assay. The IC50
was determined as 8.12 µM, which represents a potency 3.5 less than the
anti-androgen reference standard flutamide.
five studies summarised in this section (Toxicity to reproduction: other
studies) address the potentialin vitro andin vivo screening
level (anti-)estrogenic and (anti-)androgenic activity of isopentyl
The results from threein vitro studies
(Freyberger 2002a, Kunz et al. 2006, Kunz and Fent 2006), as well as the
uterotrophic assay (Krötlinger 2002), provide evidence that isopentyl
p-methoxycinnamate does not have any oestrogenic potential.
The results from an androgen receptor
binding study indicated that isopentyl p-methoxycinnamate only had weak
affinity for the androgen receptor; although a concentration response
curve was observed, the curve was flat and displacement of the ligand
did not exceed a mean of 30% (Freyberger 2002b). However, in a further
study isopentyl p-methoxycinnamate displayed multiple hormonal
activities, with positive results in the anti-oestrogenic, androgenic
and anti-androgenic assays (Kunz and Fent 2006). The relative
anti-oestrogenic and androgen activities were quite weak. The greatest
effect was found in the anti-androgenic assay, in which the
anti-androgenic potency of isopentyl p-methoxycinnamate was determined
to be 3.5-fold less than the reference compound flutamide. Noin vivo screening
data from a Hershberger assay were available, which would have clarified
whether the anti-androgenic activity measured for isopentyl
p-methoxycinnamatein vitro is also inducedin vivo.
For a substance to be considered as an
endocrine disrupter, any in vitro or in vivo screening
level activity observed must be plausibly linked to an adverse effect
observed in an apical study. Results from a 90-day repeat dose study and
a prenatal developmental toxicity study are available, which fall in
Level 4 of the OECD Conceptual Framework for the assessment of endocrine
disruption. Although these studies are not specifically designed to
detect endocrine disrupting effects, they provide relevant information
on endpoints such as weight and histopathology of the gonads, and
reproductive and developmental parameters. No effects on testes weight
or histopathology were observed in a 90-day rat oral toxicity study
(Suberg and Schilde 1987; see Section 7.5.1). The main relevant effect
found in the prenatal developmental toxicity study was increased
intra-uterine mortality at the highest dose, but this was related to the
significant maternal toxicity observed at this dose (Kemper and Jekat
1988; see Section 7.8.2). No other effects consistent with any potential
endocrine activity were observed. No gross abnormalities of the
genitalia were reported. No effects that would be consistent with a
potent anti-androgen were noted in any of these studies.
data from a two-generation reproduction study are available for
isopentyl p-methoxycinnamate, which would confirm whether there are any
longer term functional consequences from the potentialin vitro activity
observed. However, a two-generation
reproduction toxicity study is available for 2-ethylhexyl
4-methoxycinnamate, which has been submitted as a read-across study for
this endpoint (Schneiders et al. 2005; see Section 7.8.1 of this IUCLID
dataset). Wistar rats continuously treated with 2-ethylhexyl
4-methoxycinnamate at doses up to 1000 mg/kg bw/day through two
successive generations showed no adverse effects on estrous cycles,
mating behaviour, conception, parturition, lactation and weaning, sperm
and follicle parameters, macropathology and histopathology of the sexual
only potentially relevant effects observed were a slight reduction in
the number of implantation sites in the top dose F0 and F1 females and
sexual development in pups at the highest dose. However, the slightly
lower implantation rate was within the historical control range and
these effects occurred at the highest dose, at which other systemic
toxicity was observed. They are therefore considered to be secondary to
the toxicity observed at the highest dose. Similarly, lower body weight
gain in the high dose pups was considered to be the most likely cause
for the slight delay in sexual development, since body weights at the
time of sexual maturity were similar between controls and high dose
pups, and because body weight rather than calendar age is the essential
component driving sexual maturation.
full weight of evidence review of all data relevant for the assessment
of potential endocrine disruption is presented in Section 13 of this
IUCLID dossier for both isopentyl p-methoxycinnamate and 2-ethylhexyl
4-methoxycinnamate. The conclusion from this weight of evidence
evaluation is that although both substances may exhibitin vitro hormonal
activity, the evidence for adverse effects in apicalin vivo studies
is absent or weak. Based on the results of the prenatal developmental
toxicity studies and the read across from the two generation study, it
can be concluded that neither substance result in clear or consistent
adverse effects relevant for the assessment of endocrine disruption.
They therefore do not fulfil the WHO definition of an endocrine
disrupter, which requires the demonstration of relevant adverse effects
that can be plausibly linked to an endocrine mode of action.
The results obtained from the embryotoxicity/teratogenicity study in
Wistar rats indicate that isopentyl
p-methoxycinnamate is non-teratogenic and non-embryotoxic.
The lack of overt reproductive effects induced by isopentyl
further substantiated by the negative results obtained in the
uterotrophic assay in immature Wistar rats in vivo and from the androgen
and estrogen receptor binding studies.
Based on the study results outlined above, isopentyl
p-methoxycinnamate is not classified as reproductive toxicant as
specified in the current EU-CLP Regulation.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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