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EC number: 203-812-5
CAS number: 110-88-3
In a 90 day gavage study (OECD 408) no adverse signs of toxicity were observed in rats treated in the highest tested dose level (NOAEL 300 mg/kg bw/day). In a 2 week inhalation study with rats signs of respiratory irritation were observed in all exposure group. Though no signs of systemic toxicity were observed.
In a 90 day oral study, rats were
gavaged with trioxane dose levels of 30, 100, 300 mg/kg bw/day
(RCC, 2002). The assay was performed according to the current OECD 408
guideline including recovery animals in the high and control dose.
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 adverse signs of toxicity
were observed in the highest tested dose level and therefore the NOAEL
was identified as 300 mg/kg bw/day. Reticulocyte changes identified in
high dose males were interpreted as an early sign of reduced
erythropoiesis. Slight disturbance in iron metabolism was suggested by
the lower spleen weights seen in high dose males. The mean
spleen-to-body weight ratio was unchanged. Both effects were reversible at
the end of the 4-week recovery periodand not interpreted as
In a 28-day study, doses of
40, 200, 1000 mg/kg bw/day were gavaged to rats (OECD Guideline 407). A
NOAEL of 200 mg/kg bw (LOAEL 1000 mg/kg bw) was derived based on
decreased leucocyte counts and alterations of clinical chemical
parameters (e.g. increase in gamma-GT, decrease of glucose) (Hoechst AG,
1990). It should be emphazised that this value represents a very
conservative NOAEL, since the adverse character of these effects is
arguable. Reduction of absolute but not relative spleen weights was
observed in high dose males and absolute and relative spleen weights in
mid dose females. Due to lack of dose response, this effect was
The quality of study
reporting and study performance of two older 2-year chronic exposure
experiments in rats and cats was not according to current standards.
Here both studies are reported for completness but their value for an
assessment is limited.
Albino rats of mixed
strains were administered trioxane at 200 or 870 mg/kg bw day in
males and 310 or 1400 mg/kg bw day in females in daily feed
for 104 weeks (Hoechst AG, 1966).
Non-neoplastic effects in rats
were not considered to be treatment-related, since they appeared to
affect the control and treated groups to a similar extent and incidence.
No clear dose-response trends could be established in rats dying
prematurely or in those sacrificed at study termination. Therefore the
NOAEL in rats was determined to be 870 mg/kg/day in males and 1400
mg/kg/day in females (highest dose tested).
The NOAEL for cats was reported to
be 22 mg/kg bw/day in males and 23 mg/kg bw/day in females (no test
substance related findings in highest and single dose tested).
In 2 further oral repeated dose
studies female rats were exposed to 190, 580 and 1160 mg/kg bw/day for 7
weeks (Sitarek and Baranski, 1990) and male rats to 850,
1700 mg/kg bw/day for 8 weeks (Baranski, 1984).
Reversible behavioral changes in
the high dose and a dose- and time-dependent decrease in body weight
gain were observed in all treated groups in the experiment with female
rats. In the experiment with males, body weight gain was decreased and
absolute and relative weights of liver, kidney and spermatic vesicle
were increased. Histopathology of the testes revealed a dose dependent
focal necrosis of the seminiferous epithelium. Additionally in females
the oestrous cycle was significantly longer than in the control animals.
This observation was reversible and was only observed in the high dose
group in parallel to severe signs of maternal toxicity. Since reporting
is limited and no data concerning significance or correlation to other
parameters e.g. food uptake were provided, the value of these studies is
Repeated dose toxicity
In a 2 week inhalation
study, rats were whole body exposed to vapor concentrations of 0.38,
3.62 or 18.18 mg/l (Bio/Dynamics Inc., 1983). The test performance was
according to current OECD-guideline 412 and the test atmosphere was
Signs of respiratory
irritation (e.g. increased secretory responses) were observed in all
exposure groups. In the high dose group respiratory impairment and
histopathologically squamous metaplasia with necrosis and desquamation
of the mucosa of the anterior nasal cavity was observed. Due to this
reversible effect restricted to the upper respiratory tract, trioxane
was legally classified as a respiratory irritant (R37, C&L 2002).
According to GHS this would indicate classification as STOTsinglecategory
3 (H335, may cause respiratory irritation) (see acute toxicity).
For respiratory irritation a
local LOAEC of 0.38 mg/l can be determined.
Decreased relative spleen
weights were observed in all dose groups (in low dose only in males),
though due to the lack of histopathology and absolute values in the
study report no conclusion on the relevance of this observation can be
Further signs of systemic
toxicity were observed in the high dose group only (18.18 mg/l):
decrease of mean bw (13%)
in hematological parameters (e.g. increased hemoglobin, hematocrit and
erythrocyte counts, decreased leucocyte counts),
in clinical chemical parameters (e.g. increase in serum GPT, total
protein and albumin, decrease in glucose).
Based on these effects a
systemic NOAEC of 3.62 mg/l can be determined. The adverse character of this
effects is questionable and may, at least partly, be due to primary irritation
of the respiratory tract.
Additional repeated dose studies
are of such poor quality that they can not serve for a further
refinement of the NOAEC. At the most the NOAEClocalfor
respiratory irritation can be confirmed by an inhalation study with rats
exposed to vapors of 0.05, 0.5 and 2.5 mg/l (Czajkowska and Krysiak,
1983). Signs of respiratory tract irritation (e.g. increased lymphocyte
infiltration, tissue proliferation, metaplasia) were observed at the
high dose level.
When comparing the 28-day key
studies for both tested exposure routes (oral, inhalation), a good
correlation in terms of target organ toxicity (e.g. hematopoetic system)
was observed. Although, no severe sign of toxicity were identified
which would result in a classification according to EU or GHS guidance.
According to Directive 67/548/EEC and Directive 1272/2008, no
classification for systemic effects is indicated for the oral and
inhalation route of exposure. For inhalation exposure signs
of respiratory irritation require classification as a respiratory tract irritant
(R37, C&L 2002). According to GHS this would indicate classification as
STOTsinglecategory 3 (H335, may cause respiratory
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