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EC number: 604-195-9
CAS number: 1406-66-2
Repeated oral dose toxicity: - subchronic (90-day), rat (oral, gavage), NOAEL = 500 mg/kg bw- subacute (28-day), rat (oral, feeding), NOAEL ca. 1111 mg/kg bw- subacute (28-day), dog (oral, feeding), NOAEL >= 360 mg/kg bw
studies specifically conducted with RRR-(alpha-, beta-, gamma-,
been reported. Therefore, experimental data for the Vitamin E esters D-
and D,L-alpha-tocopheryl acetate are
used. Tocopherol acetates are rapidly hydrolysed to the free Vitamin E
alcohol (D- and D,L-alpha tocopherol) under physiological conditions.Please
refer to read-across hypothesis and justification for further information.
low toxicity of Vitamin E acetate after repeated administration was
supported by 28 -day feeding studies in rats and dogs (BASF 1983 and
1982). The rats were treated with D,L-alpha tocopheryl acetate at dose
levels ca. 139, 278, 556 and 1111 mg/kg bw/d and the dogs at dose levels
of ca. 45, 90, 180, 360 mg/kg bw/d in the diet.There
were no significant, substance-related differences between the groups
with regard to body weight, food consumption, and clinical-chemical,
hematological, and urine parameters. The NOAELs can be set at ≥ 1111
mg/kg bw/d in the rat study and ≥ 360 mg/kg bw/d in the dog study.
a 90-day repeated dose (oral gavage) study is available for
D-alpha-tocopheryl acetate (Abdo et al. 1986). In this study, the rats
were dosed at 125, 500 and 2000 mg/kg bw/d D-alpha tocopheryl acetate.
The relative liver weight was significantly increased in high dose
females. Administration of 2000 mg/kg bw/d caused hematological changes:
prolongation of prothrombin and activated partial thromboblastin (APTT)
times and an increase in fibrinogen value, reticulocytosis and a
decrease in hematocrit values and hemoglobin concentrations was observed
in males; APTT times were also increased in females. Hemorrhagic
diathesis was observed in males and females of the high dose group; and
increased medullary erythropoiesis was seen in the spleen of one high
test substance at all dose levels tested caused interstitial
inflammation and adenomatous hyperplasia of the lung. The lung lesions
were observed in all vitamin E-treated groups, and the incidence and
severity increased in a dose-dependent manner. These lesions were
characterized by increased cellularity, vascular congestion, thickened
alveolar walls and the presence of foamy macrophages (some of which had
undergone cell death and degeneration) in the alveolar spaces. A
lipid-like yellow pigmentation was often present within either the
macrophages or alveoli. These effects were attributed to local
aspiration of the test substance (as in the other oral gavage 90-day
study this was not observed), which would not occur under normal
these effects were not seen in the other feeding studies. Therefore, for
the NOAEL derivation the effects in the lungs were not considered.
Because at 500 mg/kg only APTT values were increased in absence of an
increase in PT and fibrinogen value, the NOAEL is set at 500 mg/kg bw/d.
the DNEL-derivation, a NOAEL of 500 mg/kg bw /d derived from the 90-day
repeated dose study with D-alpha tocopheryl acetate (Abdo,1986) study
will be used.
to EU Directive 67/548/EEC and EU Classification, Labelling and
Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008
classification is not warranted.
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