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EC number: 204-826-4
CAS number: 127-19-5
The results were not discussed by the authors.
Comment: statistically significant effects in hematology
and clinical chemistry were not evaluated concerning the toxicological
relevance. No data were given on the range of historical value for this
rat strain in this or other laboratories. Furthermore, only 6 rats per
dose per sex were evaluated concerning clinical chemistry (n=10
recommended) and hematology (n=20 recommended) for some time points only
4 -5 blood samples were assessed (e.g. clinical chemistry 12 months,
males, control or n=5 for hematology 12 months, males, control). In
summary, the relevance of these effects is questionable.
Comments on histopathology: Hypertrophy of the liver
(correlated with increased liver weight) seems to be related to
increased metabolism of the test substance and is considered not to be
an adverse effect, however, increased incidences in liver cell
degeneration and vacuolisation as well as increased pigmentation might
be adverse in view on the increased liver weight. Unfortunately, the
liver was not histopathologically examined at the low and mid dose level
complicating the derivation of an NOAEL. This problem is also unsolved
concerning the effects in the testes (atrophy, degeneration, reduced
organ weight). The other effects reported in histopathology are not
considered to be of toxicological relevance. In the reevaluation of the
histopathology (Monsanto 1990) the authors did not present data on
Monsanto (1979) performed a 2-year oral drinking water study
(equivalent to OECD 453, non-GLP) in male and female rats. Seventy
animals were exposed to the test substance diluted in water daily for
two years at concentrations of 100, 300, and 1000 mg/kg bw/day. The
water was available ad libitum. A concurrent vehicle control was
included. Animals were examined at least once daily for clinical signs
and mortality. Complete necropsy was conducted of all animals at the end
of the study. Clinical signs, effects on body weight, hematology,
clinical biochemistry, organ weights, and non-neoplastic
histopathological findings were reported to be treatment related.
Non-treatment related effect included changes in water consumption and
neoplastic histopathological findings. The NOAEC for carcinogenicity
based on the results obtained in this study was concluded to be 1000
chronic drinking water study comparable to OECD TG 453 70 Long-Evans
rats per dose per sex were treated with 0, 100, 300, or 1000 mg/kg
bw/day. At the end of six or twelve months of treatment, 10
animals/sex/group were randomly selected and sacrificed for
examinations; at the end of 24 months on test, all of the survivors were
alopecia in high dose rats no relevant clinical signs were observed. The
body weight was reduced in males at >=300 mg/kg bw/day and in females at
the high dose level of 1000 mg/kg bw/day. No effects were detected on
food and water consumption. The toxicological relevance of effects in
hematology and clinical chemistry was questionable. Urinalysis and
ophthalmology parameters were unremarkable. At 1000 mg/kg bw/day reduced
testes weight and atrophy/degeneration were seen. In males and females
of the high dose group increased incidence of liver cell degeneration,
pigmentation and vacuolisation were found. The derivation of the NOAEL
is questionable due to limitation of the histopathological assessment
(only control and high dose).
In a chronic drinking water study reduced body weight gain was reported
at >=300 mg/kg bw/day in males and at 1000 mg/kg bw/day in females; the
high dose induced liver cell degeneration in males and females and
testis atrophy in males; the (provisional) NOAEL was 100 mg/kg bw/day in
males and 300 mg/kg bw/day in females.
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