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EC number: 428-040-8
CAS number: 138261-41-3
key; M-027741-02-1 (suppl. M-027135-01-1); combined carcinogenicity +
chronic (2 years, rat, oral): NOAEL (males) 100 ppm (equivalent to 5.7
mg/kg bw/day) and NOAEL (females) 300 ppm (equivalent to 24.9 mg/kg
key; M-026310-01-1 (suppl. M-026038-01-1); carcinogenicity (2 years,
mouse, oral): NOAEL (males) 330 ppm (equivalent to 65.6 mg/kg bw/day)
and NOAEL (females) 330 ppm (equivalent to 103.6 mg/kg bw/day)
No data available.
Two reliable guideline studies are available, which both provide no
evidence for the test substance to bear any carcinogenic potential;
accordingly, no classification is warranted according to CLP Regulation
(EC) No. 1272/2008.
To assess the potency of the test item for carcinogenicity, two studies
are available, one performed in the rat and one performed in the mouse:
A 2-year combined chronic toxicity and carcinogenicity study
(M-027741-02-1 and suppl. M-027135-01-1) was performed in Wistar rats.
The study was performed under GLP condition and in accordance with OECD
TG 453 (adopted 1981). Deviations to the current version of the
guideline (adopted 2018) are considered minor and not to be expected to
have an impact on reliability of this study. The test substance was
administered via diet to 50 animals per sex and dose at levels of 100,
300, 900 and 1800 ppm, corresponding to 5.7, 16.9, 51.3 and 102.6 mg/kg
bw/day (males) and 7.6, 24.9, 73.0 and 143.7 mg/kg bw/day (females).
Control animals received plain diet. Additionally, 10 animals per sex
and dose were used for interim sacrifice after 1 year. The top dose
group (1800 ppm) was treated in a supplementary study (M-027135-01-1)
under the same conditions as compared to the main study. The aim of this
additional study was to determine the maximum tolerated dose (MTD) for
the present substance.
Analytical verification of test item stability, homogeneity and
concentration in the diet was performed.The test item was stable in the
food for 14 days and the homogeneity was confirmed, since the standard
deviations of analysed samples obtained from different areas of mixing
bottles did not exceed 10%. The achieved analytical concentration were
within a range of 98 to 100% of respective nominal concentrations.
No treatment-related effects on clinical signs, mortality, food
consumption, haematology, organ weights and gross pathological findings
were observed. Body weight gain was not affected at doses up to 300 ppm,
but slightly lower (5% in males, 8% in females) at the 900 ppm level and
significantly retarded (12% in males, 11% in females) at 1800 ppm,
compared to the controls. Also in the 1800 ppm group, significantly
increased aspartate aminotransferase (both sexes) and creatine kinase
(creatine kinase) levels were found at the terminal sacrifice. The test
item also induced formation of mineralized particles (MPs) in the
thyroid glands in both sexes. This effect was dose-dependently and
observed at the interim and final sacrifice with a NOAEL of 100 ppm in
male rats and 300 ppm in female rats, based on comparison of occurrence
of MPs in treated animals compared to historical control data. No
treatment-related neoplastic findings were observed.
Taking together in this study a NOAEL of 100 ppm (equivalent to 5.7
mg/kg bw/day) for male and 300 ppm (equivalent to 24.9 mg/kg bw/day) for
female Wistar rats was established based on the absence of adverse test
item-induced effects in the thyroid glands (mineralized particles).
Additionally, a 2-year carcinogenicity study (M-026310-01-1 and suppl.
M-026038-01-1) was performed in B6C3F1 mice. The study was performed
under GLP conditions and in accordance with OECD TG 451 (adopted 1981).
Deviations to the current version of the guideline (adopted 2018) are
only minor and not considered to have an impact on the outcome of this
study. The test item was administered via diet to 50 animals per sex and
dose at nominal concentrations of 100, 330, 1000, and 2000 ppm,
corresponding to 20.2, 65.6, 208.2, and 413.5 mg/kg bw/day (males) and
30.3, 103.6, 274.4, and 423.9 mg/kg bw/day (females). Control animals
received plain diet only. Additionally, 10 animals per sex and dose were
used for interim sacrifice after 1 year of dosing. The top dose group
(2000 ppm) was treated in a supplementary MTD finding study
(M-026038-01-1) under the same conditions as compared to the main study.
Analytical verification of test item stability, homogeneity and
concentration in the diet was performed. The test item was stable in the
food for 14 days and the homogeneity was confirmed, since the relative
standard deviation of the analyzed samples obtained from different
locations within the mixing bottle did not exceed 10%. The achieved
analytical concentrations were within a range of 96 - 102 % of nominal
No treatment-related effects on mortality, organ weights, gross or
histopathological findings were observed. Also most clinical signs
observed, such as poor general condition, rough coat, loss of hair or
increased circumference and palpable masses were considered to be
non-treatment-related since incidences were similar between groups.
However, at 2000 ppm a squeaking and twittering type of vocalization was
perceived in male and female mice from the inception of the study
onwards. Further treatment-related effects noted were a decrease of body
weight and food consumption in male and female mice. Body weight gain
was comparable to control mice at doses of up to and including 330 ppm
(both sexes), but was slightly lower at 1000 ppm (-10% for males and -5%
for females) and markedly decreased at a dose level of 2000 ppm (-29%
for males and -26% for females). This effect was accompanied by a slight
decrease in food consumption in the 1000 ppm group females (-10%), which
was even enhanced at 2000 ppm (-35% for females and -10% for males). No
effect on food consumption was observed in male mice treated with up to
and including 1000 ppm test item and in female mice treated with up to
and including 330 ppm test item. Haematological analysis revealed a
treatment-dependent decrease of leukocyte counts in the 2000 ppm dose
group (both sexes), but only in individual cases differences in e.g.
erythrocyte count, haematocrit, mean cell haemoglobin or platelet count
were observed between 1000 and 2000 ppm dose groups and the controls.
Also in the 2000 ppm group, elevated levels of alkaline phosphatase were
found in the plasma, while cholesterol levels were decreased compared to
control. No treatment-related neoplastic findings were observed. The
more common tumors were those of the Harderian gland in both sexes,
those in the liver and lung in males and those of the
haemolyphoreticular system and uterus in females. However, the spectrum
and incidence iof neoplasia in animals treated with the test item was
generally similar to that in control mice with only minor intergroup
Hence, the NOAEL obtained in this study is 330 ppm (equivalent to 65.6
mg/kg bw/day in males and 103.6 mg/kg bw/day in females) for B6C3F1
mice, based on the absence of test item-induced general toxicity noted
as a decrease in body weight at 1000 ppm.
In summary the test item was tested in two different rodent species (rat
and mouse) for its carcinogenic potential. Both studies are considered
reliable and valid and the test item was not found to possess
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