3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-benzopyran-6-yl acetate

Carcinogenicity

Description of key information

In a feed study DL-Alpha-Tocopheryl acetate was given to rats at 500, 1000 and 2000 mg/kg bw for 104 weeks (Wheldon, 1978). From this study it was concluded that the test substance has no carcinogenic effects. 

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

NOAEL

2 000 mg/kg bw/day

Justification for classification or non-classification

According 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.

Additional information

DL-Alpha-Tocopheryl acetate was fed to groups each consisting of 60 male and 60 female rats at dietary concentrations providing dosages of 500, 1000 and 2000 mg/kg body weight/day. Diet without test article served as control. After 52 consecutive weeks of treatment, ten males and ten females from each group were killed for histological examination. After 104 weeks of treatment, all surviving animals were killed.

During the first 14 weeks of treatment, prothrombin times were consistently prolonged in males (but not females) at all dosages. Persistent bleeding from minor trauma became a frequent occurrence among these animals, until the vitamin K intake was supplemented from the beginning of Week 24. All groups (including controls) received the same level of supplementation, via the drinking water (for the first three weeks) or the diet (subsequently).

Haemorrhagic incidents then declined within a few days, and prothrombin times resumed normal values. There were no other signs of reaction to treatment. Ophthalmoscopy revealed no treatment-related changes.

Impaired haemostasis contributed to the mortality among males receiving DL-Alpha-Tocopheryl acetate

at 1000 or 2000 mg/kg/day prior to vitamin K supplementation; five males died (or were killed in extremis) in each of these dosage groups during this period. A further death occurred at the highest dosage during Week 26, but infection rather than impaired haemostasis was causative.

From Weeks 27 to 52, mortality was higher among control than treated males; the total mortality for both sexes displayed no relationship to dosage at the end of the 104 -week period.

At necropsy after 52 weeks of treatment, no treatment-related macropathology was discovered. Organ weight analysis indicated only inter-group differences that were secondary to differences in bodyweight.

Necropsy of animals dying during the second half of the study or killed after 104 weeks revealed higher liver weights (when expressed as a percentage of bodyweight) in females receiving 1000 mg/kg/day. Microscopic evaluation of liver sections revealed foamy macrophages in centriacini in most (60% or more) treated females and some 15% of the treated males. In a higher proportion of cases, these macrophages yielded positive reactions to Oil-Red-O and to the Per-iodic Acid Schiff technique. The inter-group distribution of this change was clearly related to treatment with the test article but was not related to dosage.

There were small but consistently dosage-related reductions in the incidence of mammary fibroadenomas in both sexes. With this possible exception, there was no evidence of any treatment related alteration of the tumour frequency in any tissue. Occasional cases of hepatic nodular hyperplasia were discovered in all groups, including controls, and their distribution was unrelated to dosage. Therefore, it was concluded that massive dosages of DL-Alpha-Tocoperyl acetate did not have tumorigenic effects.