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EC number: 229-722-6
CAS number: 6683-19-8
The substance was found to be non-carcinogenic in a valid
carcinogenicity feeding study in mice and in a valid combined chronic
toxicity/carcinogenicity feeding study in rats (Huntingdon, 1974). Both
studies were performed prior to GLP and OECD testing guideline
introduction but are adequate in design and reporting detail. The
highest tested doses were 1000 and 10000 ppm for mice and rats,
Dosage Levels: the amount of test material in the diet was determined
periodically during the course of the study. The results of these
analyses revealed a concentration of 68-190 % of the nominal value.
No increased tumour incidence in treated rats compared to control rats:
number of tumour bearing rats: males 30/44, 19/45, 25/43 and 26/47,
females 43/49, 46/49, 45/49 and 43/50 at 0, 1000, 3000 and 10000 ppm;
tumours found for males were mainly pituitary adenomas (14/37, 5/5,
11/11, 6/37) and pancreas islet cell adenomas (2/42, 0/3, 0/2, 7/44, no
statistically significant increase); tumours found for females were
mainly pituitary adenomas (29/46, 15/17, 21/24 and 22/39) and mammary
fibro-adenomas (35/50, 36/41, 34/36 and 31/34).
The incidence of pancreatic islet cell adenomas, in male rats from the
10,000 ppm dosage group was slightly above that of the control group .
However, the increase was not statistically significant and considered
unlikely to be of biological importance. No effect was seen in female
The incidence and distribution of other neoplasms in this study were
within the normal tumour profile for laboratory maintained rats of this
strain. Briefly : mammary tumours were common in females; pituitary
tumours in both sexes; with a lower incidence of subcutaneous tumours
predominantly in males.
Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008
The available experimental test data are reliable and suitable for
classification purposes under Regulation 1272/2008. As a result the
substance is not considered to be classified for carcinogenicity under
Regulation (EC) No. 1272/2008.
The carcinogenic potential was investigated in two feeding studies. The
study in mice is chosen as key study as it was specifically designed as
a carcinogenicity study. Its procedure is equivalent to the OECD testing
guideline 451, which was published a few months prior to finalization of
that study. Its performance was supervised by the internal quality
assurance unit which is certified in the study report. Four hundred MAGf
(SPF) mice (50 males and 50 females per dose group) were treated at dose
level of 0, 100, 300 and 1000 ppm (11.7, 40.5 and 125.9 mg/kg body
weight per day for males and 10.5, 35.0 and 106.8 mg/kg body weight per
day for females) for 24 months. No clinical symptoms and no
substance-related mortality were observed. A mean daily intake of 1000
ppm did not produce non-neoplastic or neoplastic lesions and was
considered to be the NOEL. The study is valid with the following minor
limitations: The study pre-dates GLP requirements. A summary table
containing non-neoplastic lesions was not provided. The analysis
procedures/methods for the test item determination in the feed not
reported and no analysis for homogeneity. The accuracy of preparation
deviates more than 20% (7 times in total at all dose levels (4 times at
The study in rats was designed as a chronic feeding study in rats, but
in regard to the number of animals and mortality, it is similarly
suitable to assess the endpoint of carcinogenicity. Its design is
comparable to that of OECD testing guideline 453. Due to the overall low
toxicity of this substance, high doses were tested. No indication of an
increased tumor incidence or preneoplastic lesions was recorded. A total
of 500 CFY rats (hysterectomy-derived strain of Sprague-Dawley rats; 50
males and 50 females per dose group) were treated with the test article
in the diet, at dose levels of 0, 1000, 3000 and 10000 ppm in the diet
per day for 104 weeks. The doses equal 45, 135 and 446 mg/kg bw/d for
males and 55, 166 and 547 mg/kg bw/d for females based on food
conversion. The study is valid with the following restrictions: It
pre-dates GLP requirements and little details on the test item are
available. No analysis for accuracy of preparation, homogeneity and
stability were reported. The major part of the histopathological
examinations was performed 10 years after the finalization of the study
under supervision of the quality assurance unit of the test institute.
The NOEL for carcinogenicity was equal or higher than 10000 ppm.
Regarding toxicity, a NOAEL was set at 10000 ppm. An inferior bodyweight
gain among males between weeks 24 and 52 was not considered related to
treatment since no corroborative evidence was seen.
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