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EC number: 203-812-5
CAS number: 110-88-3
Toxicity to fertility:
Trioxane has not been tested for effects on fertility in
a standard OECD guileline testing protocol. However several studies are
available to address the potential effects of trioxane on fertility.
In dominant lethal assays male rats were exposed by
gavage and inhalation (Baranski et al., 1984). The assays were performed
with an exdended protocol including longer exposure times and
histopathology of the testes.
With high oral doses of 850 and 1700 mg/kg bw
trioxane for 8 weeks, no influence on reproductive parameters
(resorptions, implants, live fetuses etc.) and testes weights was
observed. Effects on fertiliy were adressed in a weekly mating design.
Although no functional deficit in fertility was recognized in males,
histopathology of testes revealed focal necrosis of seminiferous
epithelia and testicular lesions. This observation was reported in 1/10
control animals, 3/10 males of the 850 mg/kg bw dose group and 2/10 high
dose males. An unequivocal dose dependency can therefore not be
established and both dose groups exhibit significant signs of maternal
With inhalative exposure of male rats for 12 months
at a dose level of 2500 mg/m3, similarly, no treatment related effect on
male fertility was described. Furthermore no histopathological changes
in the testes were described and the study did not reveal induced
dominant lethal mutations in germ cells. Males
were mated with females at the
end of the exposure, and necropsy
of the mated females was performed on day 13/14. No
changes were seen in preimplanation
losses, dead implants, or the number of live fetuses when compared to
The effect of trioxane exposure on the oestrus
cycle of female rats was assayed following a 7 weeks gavage period with
190, 580 or 1160 mg/kg bw/day of an aqueous trioxane
solution (Sitarek & Baranski, 1990). At the high dose level (1160 mg/kg
bw/day) a reversible prolongation of oestrus cycle was observed in the 6thand
7thweek of treatment, although accompanied by signs of
toxicity, e.g. decrease in body weight, vocalization or apathy.
Therefore no effect on the female reproductive cycle was observed unless
other overt signs of toxicity occurred, providing a strong indication
that trioxane does not interfere with ovarian function. The NOAEL for
systemic toxicity in this assay was identified as 580 mg/kg bw, based on
behavioral changes. Decreased body weight was observed at the end of the
application period in all dose groups, but the adverse nature of this
effect is unclear. The value of this systemic NOAEL for a further
refinement of the repeated dose toxicity is low, since the study report
is lacking important information e.g. reversibility and food consumption.
A 90 day oral gavage study with rats was performed according to
the current OECD 408 guideline and trioxane dose levels of 30,
100, 300 mg/kg bw/day (RCC, 2002). According to the guideline this study
included a detailed macroscopic and microscopic analysis of all
reproductive organs and endocrine glands (e.g. ovaries, testes, seminal
vesicles). No significant test substance related effects were observed.
In summary the
dominant lethal assays (oral, inhal.) with an extended protocol, the
ovarian function assay and the oral 90 -day study provide
sufficient evidence, that no effects on female and male reproductive
function were observed without systemic toxicity. It is well known, that
oestrus cycle length is an indicator for more subtle impairments of
fertility (e.g. reduced pup numbers). Histopathological findings in the
testes are inconsistent and were only described in the dominant lethal
test at dose levels with signs of general systemic toxicity but not in
the 28- and 90-day studies. In rodents histopathological lesions in the
testes have been shown to be a more sensible parameter of toxicity to
fertility than male fertility indeces.
Therefore no classification for fertility is indicated, although
provided tests are not conform with current guideline test designs for
In a OECD 414 guideline study groups pregnant females were gavaged from day 7 to 20 of pregnancy. The NOAEL for developmental toxicity was 315 mg/kg bw/day based on malformations in the presence of significant maternal toxicity.
In a OECD 414 guideline study groups of pregnant female rats were
gavaged from day 7 to 20 of pregnancy (Hoechst, 1998). Trioxane was
applied as a 20% aquaeous solution in dose levels of 100, 315 and 1000
Significant maternal toxicity was observed. Decreased corrected bw
gain at all dose levels (no NOEL), and decreased absolute bw gain and
food consumption in the high dose group were reported.
The NOEL for developmental toxicity was determined to
be 100 mg/kg bw/day based on variations (retarded ossification,
increased incidence of wavy or thickened ribs). The NOAEL for developmental
toxicity was 315 mg/kg bw/day based on malformations, which were only
observed in the high dose group (aplasia of tail, sacral vertebral arch
and sacral vertebral centres). In this dose group additionaly body
weights and crown-rump length of fetuses were decreased.
Adverse developmental effects were only observed in the range of
clear maternal toxicity (1000 mg/kg bw/day).
Two additional developmental toxicity studies were published from
the polish coworkers. Both experiments were not performed according to
the OECD guideline or GLP.
In one experiment developmental effects were assayed. 22-24
pregnant rats were orally dosed with 770, 1550 and 3870 mg/kg bw
trioxane from days 8-20 of gestation (Sitarek, et al., 1988). The same
report refers to a second experiment in which 190 mg/kg bw trioxane was
Embryonic and fetal lethality, malformations and retarded fetal
development were reported in the 1550 and 3870 mg/kg bw dose groups. In
parallel severe maternal toxicity was observed indicated by reduced body
weight gain and food consumption, histopathological liver changes and
alterations in organ weights.
With 770 mg/kg bw an increase of fetuses with hydrocephalus,
retarded ossification of the sternum and incompletely developed cranial
bones were described. Only the later finding was statistically
significant and again in parallel to a 12% decrease in matenal body
weight. No effects were observed in a second experiment with 190 mg/kg
The validity of the study is considerably restricted due to
experimental deficiencies, limited reporting and an unexplained
increased incidence of morphological chances in the placenta of all
animals. Even in the lowest dose tested (190 mg/kg bw) a significantly
increased incidence of histopathological changes (21%/7%) or focal
necrosis (6%/0%) in the placentas were observed, if compared to control
In the second experiment postnatal development was assayed. 190,
580 and 1160 mg/kg bw trioxane were orally administered to pregnant rats
every second day from day 2-20 of gestation (Sitarek, et al., 1990).
The Maternal toxicity (reduced bw gain, behavioral changes) occured from
580 mg/kg bw, and at 1160 mg/kg bw the litter size was significantly
reduced and most newborn died within few days. No externaly visible
malformations were observed. Reversible behavioral changes of the pups
were only observed in doses which were toxic for the dams and no further
indications for a disturbance of postnatal development was found.
According to the Dangerous Substances Directive (67/548/EEC)
classification as a developmental toxicant is only indicated in case
developmental effects were observed without significant maternal
toxicity. This observation should result from a valid animal study.
Category 3 is indicated when methodological deficiencies limit the value
of the bioassay and an evaluation of effects can only be made with
restrictions. No classification as a developmental toxicant (or Cat. 3
at the most) is indicated in case solely minor changes of incedences of
spontaneous defects, skeletal variations or minor influence on postnatal
development of offspring were observed.
Trioxane was legally classified in Annex 1 to Directive 67/548/EEC
as Repr. Cat. 3; R63 (Possible risk of harm to the unborn child).
Based on the legal basis described above, this classification resembles
a borderline decision, since in a reliable developmental toxicity study:
mg/kg bw/day in the range of clear maternal toxicity and
lower dose levels with less maternal toxicity only variations (e.g.
retarded ossification, increased incidence of wavy or thickened ribs)
No classification for fertility is
indicated (although provided tests are not conform with current
guideline test designs for fertility).
Trioxane was legally
classified in Annex 1 to Directive 67/548/EEC as Repr. Cat. 3;
R63 (Possible risk of harm to the unborn child). Although this was
unequivocally a borderline decision as described in the summary report
of the meeting
of the commission working group on the classification
and labelling of dangerous substances (ECB
Ispra, 16 – 18 January 2002,
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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