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EC number: 639-566-4
CAS number: 165184-98-5
- A 14-day repeated dose toxicity study: NOAEL = 500 mg/kg bw/d- A 14-day repeated dose toxicity study: NOAEL = 150 mg/kg bw/d- A reproductive screening study by oral (similar to OECD guideline No. 421): NOAEL (~45-day exposure) >= 100 mg/kg bw/day.- 90-day repeated dose toxicity study by dermal: LOAEL rat > 125 mg/kg bw/day for systemic effect (both dermal and oral exposures) and LOAEL >= 125mg/kg bw/day for local effect- No data available by inhalation: no classification for STOT-RE based on the overall data on overall toxicological data and the toxicokinetics of HCA.
studies performed by oral route on α-Hexylcinnamaldehyde (HCA) were
identified as weight evidence.
study is a Reproductive
Developmental Toxicity Screening Test performed according to the OECD
No. 421 and in compliance with the GLP. HCA was administered by gavage
at 0, 12.5, 25, 50 and 100 mg/kg bw/day to male and female rats daily
for 14 days before mating, during 7 -day cohabitation period, through
pregnancy and until postpartum day 5.
both males and females were exposed to HCA for approximately a 45 -day
period. The following parameters were evaluated: viability, clinical
observations, body weights, feed weights, mating and fertility, delivery
and litter observations, organ weights, necropsy observations and
histopathology. The pups were clinically observed and weighed, and at
sacrifice, they were externally and internally examined including single
cross-sections of the head.
observed were a reduction of maternal body weight gain (22%) and food
consumption in the 100 mg/kg bw/day group on days 1 and 5 of lactation
in comparison to the vehicle control group.
conditions of this study a NOAEL of 100 mg/kg bw/day or greater was
a 14 days repeated dose study (second study), groups of Crl:CD (SD) rats
(5/sex/dose) were administered daily with alpha-hexyl cinnamic aldehyde
(HCA) at dose levels of 0 (vehicle control), 100, 250, 500 and 1000
mg/kg bw/day in corn oil by oral gavage. Animals were then observed for
clinical signs, mortality, body weights and feed consumption throughout
the study period and were all macroscopically necropsied after sacrifice
1000 mg/kg bw/day, several rats died or were euthanized after two or
three days of treatment, and dosage administration in this dosage group
was subsequently discontinued. Signs of respiratory distress (i.e.,
bradypnea, gasping), mild to severe dehydration, urine-stained abdominal
fur, decreased motor activity, ptosis, slight excess salivation, lost
righting reflex, chromorhinorrhea, chromodacryorrhea and piloerection
were observed at 1000 mg/kg bw/day; a few observations of excess
salivation occurred in males and females at 500 mg/kg bw/day. At 1000
mg/kg bw/day, net losses in body weight were observed in both sexes
during the first three days of dosage administration, with transient
reductions in body weight gain occurring at 250 and/or 500 mg/kg bw/day
during the same period. Corresponding reductions in feed consumption
occurred in male and female rats given 1000 mg/kg bw/day of hexyl
cinnamic aldehyde during the first three days of the study. Gross
pathological observation revealed irritation of the gastric mucosa in
male and female rats that died or were euthanized early in the 1000
mg/kg bw/day dosage group.
examination was limited to gross lesions, kidneys (500 and 1000 mg/kg
bw/day dose groups only), stomach, and the small and large intestines.
In the high dose one animal had mild erosion in the non-glandular mucosa
of its stomach. Several
animals had minimal or moderate tubular degeneration and/or mild tubular
these lesions were considered test substance-related. The
no effect level for the stomach and kidney changes was 500 mg/kg bw/day. The
other gross and microscopic findings were considered incidental,
commonly observed in controls of this strain and age of rats, and were
considered unrelated to the administration of HCA.
Severe clinical signs, mortality, reduced
body weight gain, reduced feed consumption, pathological signs of
gastric irritation and microscopical changes in stomach and kidneys were
observed at 1000 mg/kg bw/day. Under the test conditions, the No
Observed Effect Level (NOEL) of hexyl cinnamic aldehyde in rats was
considered as 250 mg/kg bw/day while the No Observed Adverse Effect
Level was determined at 500 mg/kg bw/d based on the clinical effects,
i.e. excess salivation and mild dehydration.
third study, HCA was administered orally by gavage to albino rats at
150, 375, 750, 1000 and 1500 mg/kg bw for 14 consecutive days.
died after three days of treatment at 1500 mg/kg bw/d. Profuse
salivation occurred in the majority of animals following daily gavage.
Body weights did not appear to be affected by the administration of HCA
at the dose levels investigated. Gross pathological observation revealed
mild to moderate irritation of the gastric mucosa in all groups with the
exception of three animals treated at the 150 mg/kg bw/d level. These
effects were considered as local effect due to simple destruction of
conditions of this study a NOAEL of 150 mg/kg bw/day is determined based
on the local effects on the gastric mucosa.
studies conducted on α-Amylcinnamaldehyde (ACA) were considered as
relevant based on a read-across approach. In fact, HCA and ACA are
alkyl-substituted cinnamaldehyde derivatives. Common structural features
of these substances are that they contain a 3-phenyl-2-propenal backbone
as illustrated in attached file. HCA and ACA are rapidly absorbed from
the gut, metabolized and excreted primarily in the urine (within 24
hours) and, to a minor extent, in the faeces. The position and size of
the substituent do not significantly affect the pathways of metabolic
detoxication of cinnamyl derivatives. Therefore, Cinnamyl derivatives
containing α-alkyl substituents, such as HCA and ACA, are
extensively metabolized via β-oxidation followed by cleavage to
yield mainly the corresponding hippuric acid conjugate excreted in the
urine (see § 7.1). An illustration of the metabolic pathway is included
as attached background material. However,
larger substituents located at thealpha-position (like HCA)
inhibitsbeta-oxidation to some extent and are excreted primarily
unchanged or as the conjugated form of the cinnamic acid derivative.
these supporting studies showed an absence of effect up to 30 mg/kg bw/d
in a 90-day repeated dose oral toxicity study while, at the highest dose
(c.a.300 mg/kg bw/day), a slight but statistical significant increase in
the relative weight of the liver and the kidneys may be considered of
low toxicological concern. Therefore, the
results obtained with ACA were consistent with those observed from the
HCA testing studies.
conclusion, the available data are considered adequate for the purpose
of classification and labelling.Considering
the overall results of studies and their consistency, no
classification is justified for HCA regarding specific target organ
toxicity - repeated exposure since no specific target organ for
significant toxicity is identified, i.e.at the limit dose of
classification (≤ 100 mg/kg bw/d for 90-day exposure).
studies performed by dermal route on Hexylcinnamaldehyde (HCA) were
identified as weight evidence.
range-finding study of the 90-day repeated dose toxicity described
below, HCA was applied percutaneously to the shaved dorsa of 10 male
Sprague-Dawley rats at dose levels of 0.15, 0.375, 0.75, 1.5 and 3.0
g/kg bw/day for 28 consecutive days.
and eschar formation with cracking and dryness of the skin at the test
article application site were noted at all dose levels.
Hyperirritability was noted at 0.75, 1.5 and 3.0 g/kg and abnormally
arched backs at 1.5 and 3.0 g/kg bw/d. The two high dose (3.0 g/kg) rats
developed ataxia and survived only 7 and 11 days of treatment. Body
weights and food consumption differed little at the 0.25, 0.375 and 0.75
g/kg bw/d dose levels. At 1.5 and 3.0 g/kg bw/d, body weights were
reduced substantially but food intake was depressed only at 3.0 g/kg
comparison with respect to blood biochemical parameters revealed a
dose-related negative effect on clotting time and white blood cell
count. The 1.5 and 3.0 g/kg levels demonstrated a marked shift in the
proportion of segmented neutrophils to lymphocytes. A reveiw of the
various blood biochemical parameters investigated, suggested an adverse
dose-related effect revealed by a progressive increase in BUN, SAP and
SGPT values. The SGOT and Glucose values indicated a dose-related trend
(decrease in Glucose and increase in SGOT) especially in group 3 (0.75
g/kg bw/d) and 4 (1.5 g/kg bw/d).
pathological examination revealed local effects such as thickening of
the skin at the application sites for the dose levels 0.375 and 0.75
g/kg bw/d. At 1.5 g/kg bw/d the test article caused thickening of the
skin and erythema of both the dermis and epidermis along the lateral
aspects of the application site.
of HCA at 3.0 g/kg bw/d produced dry and cracked skin at the
administration site, body emaciation, congested lungs and
gastrointestinal irritation. Both absolute and relative organ weight
data displayed decreases in the weights of the thymus and spleen at 1.5
g/kg and other treated groups. The relative organ weight data for the
gonads (right and left) displayed slightly heavier weights at the 1.5
g/kg dose level. Microscopic examination of the skin at the application
dose levels except 0.15 g/kg bw/d. At 0.75 and 1.5 g/kg bw/d, kidney
alterations consisting of focal dilation of the tubules were noted.
Congestion of the gastrointestinal tract with sub-acute to chronic
necrotizing and hemorrhagic enteritis of the small intestine was
observed at 3.0 g/kg. Lymphoid depletion and necrosis with
reticulo-endothelial hyperplasia were observed in one animal at 3.0 g/kg
sub-chronic toxicity study performed similarly to OECD guideline No. 411
(main study following the range-finding study above), HCA was
administered percutaneously to rats at 125, 250, 500 and 1000 mg/kg
bw/day for 90 consecutive days. For control purposes, a control group
was maintained without treatment.
administration of HCA resulted in dose-dependent dermal irritation
characterized by erythema, cracking, dryness and sloughing. Five male
and three female rats did not survive 90 days of treatment at 1000 mg/kg
bw/d. Significant changes in the body weights, the absolute food
consumption and the absolute food intake were observed in animals
treated at both highest doses.
and clinical biochemistry were recorded after 13 weeks of test article
administration. Urinalysis data obtained during the conduct of the study
examination at necropsy revealed dose-related irritation of the
gastrointestinal tract mucosa and the treated skin. The liver and kidney
weights of treated females were significantly increased at 250, 500 and
1000 mg/kg bw/d. Histopathological examination revealed morphological
alteration at the 1000 mg/kg bw dose level in the form of hepatic
hydropic vacuolization and single cell degeneration, splenic lymphoid
depletion and fibrosis, focal gastric ulceration and chronic necrotizing
dermatitis. Bone marrow examination revealed dose-related increase in
the myeloid-erythroid and decrease of the cell-fat ratios. These results
represented systemic effects while local effects were also observed
since application of HCA induced cracking and dryness of the skin in all
the treated animals
studies described above (the range-finder and the main study), the
authors suggested that the gastrointestinal irritation observed at the
highest tested doses was a consequence of HCA intake during grooming and
ingestion of necrotic skin. Indeed neither coverage nor restrainers were
used to prevent ingestion during the rat skin exposure. Therefore, the
gastrointestinal irritation should be considered as local effect due to
oral exposure to HCA. Moreover, this assumption is consistent with the
irritation observed at the highest doses in the repeated dose oral
toxicity study (see § 7.5.1). Systemic effects observed at this dose are
more likely the consequence of HCA ingestion rather than the results of
HCA skin application itself. Finally, the skin absorption potential of
HCA which is estimated to be very low (0.183 %, see §7.1.2) supports
the observed effects, a LOAEL of 125 mg/kg bw/d can be set for local
effects based on skin irritation while a relevant LOAEL for systemic
effects cannot be determined since the animals were exposed both by
dermal and oral route. However, as no systemic effect was observed at
125 mg/kg bw/d, it is assumed that the LOAEL for systemic effect by
dermal route is likely much higher than this dose and therefore higher
than the dermal dose limit of the CLP classification (≤ 200 mg/kg bw/d
for 90-day exposure).
third repeated dose dermal toxicity study, HCA (5% purity in phenyl
ethyl alcohol) was applied to the shaved skin of Sprague-Dawley Albino
rat (5/sex/dose) at dose level of 25 mg/kg bw/d (0.5 mL/kg), daily, 7
days/week during a 90-day period. A control group received phenyl ethyl
alcohol alone (1.0 mL/kg).
were observed daily and skin reactions were recorded. Body weights were
recorded weekly. At termination, selected hematology, clinical chemistry
and urinalysis parameters were evaluated. All animals were examined
grossly and liver and kidneys were weighed. Microscopic examination of
the skin, liver, kidney, sterna bone marrow and spinal cord was
rat treated with HCA died on Day 14. At necropsy, there was evidence of
a lung infection. The death was not considered to be related to treatment.
were no dermal reactions observed on any rats in any group.
the conditions of the study there was no evidence of toxicity induced by
treatment with HCA. The NOAEL is therefore 25 mg/kg bw/d, i.e. the
highest dose tested.
the overall available data are considered adequate for the purpose of
classification and labelling.Considering
the results of both studies and their consistency,does
not justify the classification of HCA for specific target organ toxicity
- repeated exposure since no specific target organ for significant
toxicity is identified,i.e.at the limit dose of classification.
No data is
available for chronic exposure by inhalation to HCA or by of its
analogues. However, an acute toxicity study was performed in rats
exposed by inhalation to aerosol of HCA (Klimisch 2, see §7.1.2).The
animals were exposed to HCA aerosol form respirable particles of 1.3 µm
diameter at 5 mg/L nominal concentration (2.12 mg/L actual
concentration), for four hours. None of the animals died during exposure
and following the 14-day observation period. Moreover, there were no
clinical changes of possible toxicological significance. However,
enlarged bronchial lymph nodes sometimes accompanied by pulmonary
congestion, or multiple grey-green pinpoint foci in the lungs were
recorded and considered as local effects.
account the relevant physico-chemical properties of HCA for inhalation
such as the log Pow = 5.3 (see §4.7) and the water solubility = 1.62
mg/L (see § 4.8), HCA is a lipophilic liquid slightly soluble in water
which is consistent with the available toxicokinetics data. Therefore,
it is assumed that during exposure by inhalation, HCA is likely absorbed
at the alveolar level and then, metabolized via β-oxidation and excreted
primarily in the urine (within 24 hours) and, to a minor extent, in the
faeces in the same way that occur after oral absorption (see §7.1). It
is unlikely that repeated exposure by inhalation induces target organ
toxicity at the limit of classification by inhalation according to the
CLP (≤ 0.2 mg/L for 90-day exposure).
harmonized classification is available according to the Regulation (EC)
No 1272/2008 including ATP1.
The available data are considered adequate
for the purpose of classification and labelling. The evidence available
does not justify the classification of alpha- Hexylcinnamaldehyde for
specific target organ toxicity - repeated exposure. No specific target
organ for significant toxicity is identified.
No self-classification is proposed according
to the Directive 67/548/EEC and the Regulation (EC) No. 1272/2008 (CLP
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