Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 203-161-7
CAS number: 103-95-7
and Cyclamen acid plasma concentration after 28 days gavage dosing
Cyclamen aldehyde (CA) has been widely used for the last 100 years
as a muguet note in perfumery. The safe use of this material is well
established through the understanding of exposure and based on
quantitative risk assessment confirmed by the RIFM Expert Panel, which
is supported by a wide range of toxicology studies conducted over the
last 20 years. Repeated dose studies in rats that were mainly conducted
for the purposes of hazard identification for the REACH registration,
revealed adverse effects on sperm maturation leading to impaired
fertility. The effect on spermatogenesis appears to be linked to the
main circulating metabolite, 4-isopropyl-benzoic acid (iPBA). However,
metabolism studies in rat, rabbit and human primary cultures of
suspended hepatocytes, indicated species differences with iPBA readily
formed by rat hepatocytes but below detection limit in cells from
rabbits and humans. In plated rat hepatocytes, iPBA is detected as
Coenzyme A-conjugate and this conjugate (iPBA-CoA) accumulates to stable
levels over 22 h. It has been shown, that in vitro accumulation of
CoA-conjugates is a metabolic hallmark strongly correlated to male rat
reproductive toxicity for a number of structurally related compounds.
iPBA-CoA is also formed in vivo both in the liver and in the testes of
rats dosed with CA. iPBA-CoA does not accumulate in plated rabbit and
human hepatocytes where it is rapidly cleared within 22 h. In a rabbit
in vivo study, no effects of CA on spermatogenesis were observed. Thus,
a species specific metabolic fate linked to CA toxicity in male rats can
be postulated based on analytical data in vitro and in vivo in the
liver, and in male reproductive tissue in vivo. There is strong evidence
that this species specific metabolic fate in the rat is not relevant to
the rabbit, which is a non-responder species. Finally, lack of
accumulation of iPBA-CoA in human hepatocytes indicates that like the
rabbit, humans are unlikely to be vulnerable to iPBA hepatic and
In vitro studies (hepatocyte suspensions and plated hepatocytes)
from multiple species (mouse, rat, rabbits and humans) and in vivo
studies in rats have been conducted to examine the metabolism of CA
(manuscript in preparation). Metabolites of CA are widely distributed in
vivo being found in the plasma, liver and testes. In vitro, five major
metabolites were detected - the direct oxidation product cyclamen
carboxylic acid and several glucuronide conjugates including a direct
glucuronide of the aldehyde, the glucuronide of cyclamen alcohol as well
as the glucuronide of a hydroxylated cyclamen alcohol. Cyclamen alcohol
itself was not detected by LC-MS. These metabolites occurred at high
levels in all four species. In rats, cyclamen carboxylic acid was also
further degraded to 4-isopropyl-benzoic acid (iPBA). Levels of this
metabolite was below detection limit in mouse, rabbit and human
hepatocyte incubations, indicating a species difference in the
metabolism towards iPBA.
In plated primary hepatocytes from rats, metabolism to iPBA is
fast and this intermediate is further conjugated to Coenzyme A (CoA).
This CoA conjugate (iPBA-CoA) is rapidly formed and, remains at constant
levels for the entire duration of the experiment (22h). In plated rabbit
and human hepatocytes, an initial formation of iPBA-CoA is also
detected. However, this metabolite is cleared over time, and only low
levels are detected after 22 h. These data clearly indicate that in
rats, a sustained accumulation of iPBA-CoA conjugate is observed, which
is not the case in hepatocytes from rabbits and humans.
Plasma and tissue samples from rats exposed to CA for 28 days
demonstrate metabolism data that is consistent with in vitro results.
Plasma samples showed a high circulating level of iPBA (264.6 ± 85.4 uM,
combined free iPBA and its glucuronides) and iPBA and its glucuronides
are the main circulating metabolites of CA. Analysis of the tissue
samples indicated that a high amount of iPBA-CoA had accumulated in the
liver and iPBA-CoA was also detected in the testes, albeit at much lower
concentrations. Further detailed analysis of the different samples with
LC-HRMS allowed drawing a tentative in vivo metabolic map. Oxidation of
CA to Cyclamen carboxylic acid and then to iPBA on the one hand, and
hydroxylation of Cyclamen carboxylic acid are two key metabolic
pathways. From iPBA, multiple secondary metabolites are formed,
including conjugates to glucuronic acid, glycine, glutamate, carnithine
and taurine. The acyl glucuronide and the glycine conjugate of iPBA were
the most abundant phase II metabolites of CA detected in plasma. The
acyl glucuronide of iPBA is, in addition to iPBA, an important
metabolite in the testes and was also detected in liver samples.
It is expected that the various glucuronide conjugates would be
excreted into bile and urine. Glucuronide conjugates are extensively
excreted via bile, and glucuronide conjugate metabolites of BMHCA, a
read-across molecule to CA have been observed in urine of rats.
-Natsch et al., "A species specific
metabolism leading to male rat reprotoxicity of cyclamen aldehyde: in
vivo and in vitro evaluation",Food and Chemical
-Laue et al., "Benzoyl‑CoA conjugate
accumulation as an initiating event for male reprotoxic effects in the
rat? Structure–activity analysis, species specificity, and in vivo
relevance", Archives of Toxicology, 2020.
-Laue et al., "p-Alkyl-Benzoyl-CoA Conjugates as Relevant Metabolites
of Aromatic Aldehydes With Rat Testicular Toxicity—Studies Leading to
the Design of a Safer New Fragrance Chemical", Toxicological Sciences,
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.
På den här webbplatsen används kakor. Syftet är att optimera din upplevelse av den.
Welcome to the ECHA website. This site is not fully supported in Internet Explorer 7 (and earlier versions). Please upgrade your Internet Explorer to a newer version.
Do not show this message again