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EC number: 203-161-7
CAS number: 103-95-7
Cyclamen aldehyde is oxidised to p-isopropyl-benzoic acid (iPBA) and
further transformed to the coenzyme A conjugate 4-iPBA-CoA (p-iPBA-CoA).
Coenzyme A conjugates are intracellular metabolites, which cannot be
secreted and thus do not reach circulation, while the small acid 4-iPBA
and conjugates of 4-iPBA with amino acid or glucuronide can potentially
enter the bloodstream after being formed in the liver. Different
chemicals acting as metabolic precursors of p-alkyl benzoic acid
derivatives such as 4- iPBA have been found to affect spermatogenesis
and reproductive capacity in male rats. These chemicals are efficiently
transformed to p-alkyl-benzoyl Coenzyme A (CoA) conjugates in plated rat
hepatocytes. A strong correlation was found between the reprotoxic
potential and the ability of the chemicals to form p-alkyl-benzoyl CoA
conjugates in liver cells [Laue, H., et al.,2017. However, so far most
metabolic investigations were conducted in liver cells and not in cells
from reproductive tissues and limited in vivo data are available.
Therefore, the objective of this study was to determine the toxicity on
reproductive organs of male Wistar Han rats treated for 28 consecutive
days by daily oral gavage at dose levels of 0, 30, 100 and 300
mg/kg/day. In the current study, clinical signs, body weights, food
consumption, sperm analysis, gross necropsy findings and histopathologic
examinations (testis only) were evaluated and correleted with
circulating blood concentration of metabolites of Cyclamen Aldehyde,
CoA-conjugate formation in tissue samples (testes and the liver), as
well as the metabolite profile in tissue samples of the testes and the
Male Wistar Han rats were treated with Cyclamen Aldehyde for 28
consecutive days by daily oral gavage at dose levels of 0, 30, 100 and
This current study indicates that 4-iPBA and the glucuronide conjugate
of 4-iPBA are major circulating metabolites in the plasma of rats dosed
for 28 days with cyclamen aldehyde especially at 300 mg/kg/day, where
significant effects on sperm formation are observed. 4 - iPBA is
efficiently conjugated to coenzyme A in the liver leading to high levels
of this CoA conjugate. In the testes, the target organ for male
reproductive toxicity, iPBA-CoA was also found, but at substantially
lower concentrations. Different iPBA conjugates are detected in the
plasma and in testes and liver (glucuronide-, glycine-, taurine-
carnitine- and glutamic acid-conjugates) with glucuronides as major
Phase II metabolites. Cyclamen aldehyde is easily oxidized to the
corresponding acid (M2), but this is only a minor intermediate. It is
either directly degraded to iPBA and then hydroxylated, putatively at
the isopropyl-side chain (M8). Alternatively, the acid M2 can directly
be hydroxylated to M5 which is a further important metabolite, and then
degraded to the hydroxylated iPBA (M8) or further oxidized (M6). In both
cases, the hydroxylated metabolites is conjugated, especially to
glucuronic acid. Given that 4-iPBA is the putative toxic metabolite,
pathway may be a competing detoxification pathway.
No mortality occurred in the study and there were no toxicological
relevant clinical signs observed.
Slightly lower body weight and body weight gain were observed in males
at 100 mg/kg/day. The body weight and body weight gain in males at 300
mg/kg/day were moderately decreased (achieving statistical significance
for body weight on Day 29). At the severity observed, the body weight
effects at 300 mg/kg/day were considered to be adverse, but the effects
at 100 mg/kg/day were considered not to be adverse. Food consumption did
not reveal any test item-related effects.
During sperm analysis, test item-related changes in motility,
concentration and morphology were observed at 100 and 300 mg/kg/day.
These consisted of a lower percentage of motile sperm and progressive
sperm and number of cells with a normal morphology and coiled tail and
an increase in number of cells with a detached head and abnormal neck at
100 mg/kg/day. At 300 mg/kg/day, the effects on sperm motility,
concentration and morphology were similar compared to 100 mg/kg/day, but
more severe. The changes in percentage of motile sperm and progressive
sperm at 300 mg/kg/day were statistically significant. Additionally,
decreased total sperm count in the epididymis and an increase in number
of cells with abnormal heads and combined cells were observed at 300
mg/kg/day. In 3 out of 5 males at
300 mg/kg/day insufficient amount of cells were present to determine
sperm cell morphology. The effects observed at sperm analysis at 100 and
300 mg/kg/day were considered to be adverse.
At necropsy, a focal nodule (soft, yellow) was noted unilaterally in the
tail of the epididymis in 3 out of 5 males at 300 mg/kg/day. This
finding is suggestive for sperm granulomas, however, the exact nature of
this macroscopic change requires histological evaluation, which was not
included in this study. Based on the type of finding and incidence, this
finding was also considered test item-related and adverse.
At histopathological examination of the testis, degeneration of
elongating spermatids and spermatid retention was observed in all males
at 300 mg/kg/day. In addition, degeneration of round spermatids
was prominent in one male at 300 mg/kg/day. The combination of
histologic changes noted in the testis at 300 mg/kg/day is suggestive of
a test item-related abnormality in spermiogenesis (transformation of
round spermatids to mature, elongated spermatids) and spermiation
(release of mature spermatids from the seminiferous epithelium)
(O’Donnell, 2014). These changes correlated with the changes observed in
analysis, including lower sperm concentrations, and morphologic
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