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EC number: 639-566-4
CAS number: 165184-98-5
No other data available
position paper was written for the toxicity to reproduction: see
"Toxicity to reproduction, waiving" (§7.8.1) . The conclusion is
14-day repeated-dose toxicity studies described in § 7.5.1 showed marked
toxicity (both systemic and local effects) at 1000 mg/kg bw/d.
Furthermore, the findings observed in the reproduction screening test
(similar to OECD TG 421) showed that the highest dose level of 100 mg/kg
bw/day can be considered as the maximum tolerated dose (MTD) for the
dams. Therefore, both studies can contribute to a decision on further
testing requirements, i.e. a two-generation study, based on aWeight
of Evidenceassessment. In fact, the purpose of
Reproduction/Developmental Toxicity Screening Test provided information
on the effects on male and female reproductive performance such as
gonadal function, mating behaviour, conception, development of conceptus
and parturition. Although the exposure duration of this study may not be
sufficient to detect all effects on the spermatogenic cycle, it was
assumed that in practice the 2-week exposure period would be sufficient
to detect the majority of testicular toxicants (Ulbrich & Palmer, 1995).
Furthermore, an evaluation of the OECD TG 421 has confirmed that this
type of test was useful for initial hazard assessment and could
contribute to decisions on further testing requirements (Reuteret al.2003,
Gelbkeet al.2004). Therefore, the absence of adverse effects on
reproduction or on reproductive organs up to 100 mg/kg bw/d HCA
(considered as MTD) in the reproduction screening test together with the
strong toxicity of HCA observed at higher doses in the 14-day repeated
dose toxicity study were sufficient to meet the information needs for
non-classification for toxicity to reproduction. This being the case, it
is not useful to conduct of a two-generation study as required at the
Annex IX level.
- WoE (alpha-hexylcynnamaldehyde): reproduction/Developmental toxicity screening test (similar to OECD 421): NOAEL >=100 mg/kg bw/day for developmental toxicity in rats.- WoE (cynnamaldehyde): short-term in vivo screening test based on proposal by Chernoff & Kavlock (1983): NOAEL >=1200 mg/kg bw/day for developmental toxicity in mice.- WoE (cynnamaldehyde): pre-natal (segment II) toxicity study following the protocol of the Japanese guidelines: LOAEL = 5 mg/kg bw/day for developmental toxicity in rats.- WoE (cinnamic acid and cinnamic alcohol). Russian developmental toxicity studies of non-standard design: NOAEL >=50 mg/kg bw/day for developmental toxicity in rats for both substances.
Regarding the developmental toxicity
assessment for alpha-hexylcynnamaldehyde (HCA), several studies
performed with HCA (one study) and with analogues (Cynnamaldehyde,
cynnamic acid or cynnamic alcohol) were considered collectively using aWeight
of Evidenceapproach to establish the most relevant endpoint and its
The analogue approach can be
considered as HCA has been evaluated within the "Cinnamyl derivatives"
category by the Flavor and Fragrance High Production Volume Consortia in
its submission to the US Environmental Protection Agency (Submission
dated 05Mar2005, see attached document “FFHPVC” §7.1.1), and by the
World Health Organisation in its Cinnamyl Alcohol and Related Substances
review presented in the WHO Food Additives Series 46 (see attached
document, WHO §7.1.1).
The grouping of Cinnamaldehyde and HCA
into the “Cinnamyl derivatives” category is based on their structural
relationships and the resulting similarities of their physico-chemical
(as described in Table 7.1/1) and toxicological properties (see FFHPVC,
2005). Based on this grouping approach, studies on Cinnamaldehyde, its
tautomer alcohol (Cinnamic alcohol) and their corresponding acid
(cinnamic acid) were considered reliable to assess the toxicological
profile of HCA (see attached figure “Metabolism of cinnamaldehyde
derivatives” in §7.1.1).
A summary of the different studies is
In the dosage-range finding study
conducted similarly according to guideline OECD 421 (Lewis 2010), rats
were given once daily by gavage HCA diluted in corn oil at 12.5, 25, 50
or 100 mg/kg bw or the vehicle alone. The males were treated from 14
days before cohabitation, through mating (maximum of 7 days), and
continuing through the day before sacrifice on day 47. The female rats
were administered HCA (same dosage as for males) or vehicle two weeks
before cohabitation, through mating, and continuing through the day
before sacrifice on day. Female rats were allowed to deliver their
litters and were sacrificed on postpartum day 5 (PPD 5). F1 generation
pups were also sacrificed on PPD 5 (i.e.5thday of
lactation). The following parameters were evaluated: viability, clinical
observations, body weights, feed weights, mating and fertility, delivery
and litter observations, organ weights (epididymes, ovaries, prostate,
seminal vesicles, testes, and uterus with cervix), necropsy observations
and histopathology (epididymes, ovaries, prostate, seminal vesicles,
testes, and uterus with cervix).
All P generation male and female rats
survived to scheduled sacrifice. There were no treatment-related
clinical observations or gross lesions in the P generation rats of both
sexes at any dosage level tested. In addition, none of the microscopic
findings examined were considered related to treatment withHCA.
Body weights and body weight gains of the treated P generation male rats
were generally comparable among the dosage groups. Absolute and relative
feed consumption values in male rats were unaffected by treatment withHCAduring
the entire dosage period.
There was no effect of HCA
on estrous cycling. There was no effect on mating and
fertility (fertility index, gestation index, number of implantation
sites) at any dosage level tested. All recorded pregnant rats (7, 8, 7,
8 and 6 females in the five respective dosage groups from the control
group to the highest dose group) delivered a litter. Natural delivery
and litter observations (duration of gestation, number and sex of
offspring per litter, stillbirths, live births, gross alterations,
litter size and viability, viability index, lactation index, percent
survival, sex ratio, pup body weights) were unaffected by dosages of HCA
as high as 100 mg/kg bw/day. No treatment-related clinical
or necropsy (including a single cross-section of the head and
examination of the cross-sectioned brain for apparent hydrocephaly)
observations occurred in the F1 generation pups. As such, no
developmental effects were observed.
The NOAEL for developmental toxicity
was 100 mg/kg bw/day or higher under the test conditions of this study (Lewis,
In a preliminary developmental study
testing 60 chemicals, a dose of 1200 mg/kg bw/day of cinnamaldehyde was
administered once daily by gavage to mice from days 6 -13 of gestation.
The selected dose represented the predicted maternal LD10. Dams were
allowed to deliver their litter around day 18 of gestation. Maternal
body weights were recorded on gestation days 6, 17 and day 3 postpartum.
Number of live pups and weight of pups was recorded on postnatal days 1
and 3. Reproductive endpoints were maternal weight change, litter size,
birth weight and neonatal growth and survival to postnatal day 3.
Cinnamaldehyde induced no effect on
maternal survival, maternal bodyweight gain and viable litters. Neonatal
response showed no difference on liveborn / litter and percentage
survival. Birth weight and weight gain was were normal for all pups.
Following the classification used by Chernoff and Kavlock,
cynnamaldehyde was recorded in the group of those that had no effect.
Results in this assay and conventional mouse teratology tests were
concordant. Conventional data were available for 14 chemicals (ten
teratogens, one fetotoxin, three non teratogen) of which 11 (nine
teratogens, one fetotoxin and one non teratogen) produced evidence of
developmental toxicity. Therefore, cynnamaldehyde was considered as low
priority candidates for conventional testing on the basis of results.
Under the test conditions, no maternal
toxicity and no development effect was observed at the highest dose
tested. The No Observed Effect Level was higher than 1200 mg/kg bw/d for
maternal toxicity and development toxicity in mice (Hardin, 1987).
In a study (Mantovani, 1987) conducted
following the Japanese protocol for drug toxicity studies (Segment II
pre-natal toxicity study), female rats (15 to 17/group) were
administered cinnamaldehyde once daily by gavage at 0, 5, 25, and 250
mg/kg bw from days 7 to 17 of gestation and then killed on day 20.
Weight and food consumption were recorded on days 0, 7, 18 and 20.
Significantly lower weight gain was
observed between days 7 and 20 in the dams at the two highest dose
levels without a concurrent decrease in food intake and effect on
relative liver or kidney weight. The lowered weight gain was the only
sign of maternal toxicity even if it was not dose-dependent and probably
not related to a difference in liver metabolism and renal function
reducing maternal performance.
No effects on embryolethality or gross
abnormalities were observed.
There was a significant increase in
pre-implantation loss in the controls in comparison with the treated
groups: index of affected corpora lutea on the basis of 'total foetuses'
were 35, 11, 8, and 14, for controls, 5, 25, and 250 mg/kg bw/day for
Very few gross malformations of
foetuses were observed. Examination of the skeletons and soft tissues
showed that several parameters were significantly increase in treated
groups in comparison with the controls
Increase in incidence of poor cranial
ossification, dilated ureters and renal variations observed in the 5
mg/kg bw/day, in contrast to the lowest observed effect level of 25
mg/kg bw/d in the dams, may indicate that the fetus was slightly more
sensitive to cynnamaldehyde toxicity than in the adult. However, without
evidence of dose-related trend together with the absence of historic
control data and the absence of the fetal length these results may not
be considered as of toxicological concern.
Under the test conditions, LOAEL of 25
mg/kg bw/day for maternal toxicity and a LOAEL of 5 mg/kg bw/day for
developmental toxicity could be concluded in this study. However some
important data were not available in the publication such as the fetal
length which is necessary to determine the time of ossification taking
into account both the fetal weight and the fetal length. Furthermore,
historical control data are always necessary to determine the
acceptability of the concurrent control group, to establish the
incidence ranges for frequently and rare occurring morphological
changes, to detect the “clusters” of abnormalities. Therefore, the
slight abnormalities observed at the lowest dose in this study which
mainly represented delay in development may not be relevant in regard to
developmental toxicity assessment.
In a non-standard design study were
given cinnamyl alcohol orally at a dose of 53.5 mg/kg bw /day or
cinnamic acid at a dose of 0, 5, or 50 mg/kg bw/day throughout
gestation. On day 20 of gestation, 50% of the treated and control
animals were sacrificed, and their fetuses were removed for examination.
Fetal body weight, liver nucleic acids, number of survivors, and bone
development did not differ significantly between test and control
groups. The remaining females from both groups were allowed to deliver
normally. Again, the body weights, number surviving, and size and
general development of offspring at birth or at 1 month did not differ
significantly between treated and control groups (Zaitsev & Maganova,
Therefore, information is available
from a variety of animal studies summarized above, which give different
amounts of direct and indirect information on the potential reproductive
toxicity of HCA:
study similar to OECD TGs 421 ( HCA tested)
short-termin vivo screening test,e.i.similar
Chernoff/Kavlock test (cynnamaldehyde tested),
developmental toxicity test: pre-natal (segment II) toxicity study
following the protocol of the Japanese Ministry of Health and Welfare,
Pharmacological Affairs Bureau, 1984. (cynnamaldehyde tested),
developmental toxicity studies of non-standard design (cinnamic acid and
cinnamic alcohol tested).
Interpreted with caution (as described
above), the overall results didn’t show any concern for developmental
toxicology of HCA at dose levels where maternal toxicity was not
observed in both screening studies (similar OECD 421 guideline study and
similar Chernoff/Kavlock test) even if these studies don’t provide
complete information on all aspects of reproduction and development.
However, it is important to report that workshop participants (workshop
sponsored by the National Institute for Occupational Safety and Health)
viewed the Chernoff/Kavlock test as highly reliable in correctly
identifying developmentally toxic chemicals and suggested that a
negative finding could be a sufficient basis for regulatory agencies to
determine that conventional teratology tests in the same species are not
warranted (Hardin et al. 1987). Moreover, the available prenatal
developmental toxicity studies, even if not reliable based on the
absence of historical control data (Mantovaniet al.1989) or
details on protocol (Russian studies), provided an indirect focused
evaluation of potential effects of HCA (since cynnamaldehyde, cynnamic
acid and cynnamic alcohol were tested) on prenatal development only
represented by delay of ossification and renal variations.
In conclusion, the Weight of Evidence
assessment involves the consideration of all data that are available and
are relevant to demonstrate the absence of developmental toxicity
concern for HCA
Moreover, HCA is naturally occurring
substances, and it is already used as common component of traditional
foods and generally recognized as safe (GRAS) as flavoring substances by
the U.S. Food and Drug Administration (US FDA) and as food additives by
the World Health Organization (WHO) for years. HCA are also used in
fragranced consumer products such as soaps and cosmetics.
No self-classification is proposed according
to the Directive 67/548/EEC and the Regulation (EC) No. 1272/2008 (CLP
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