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EC number: 201-121-3
CAS number: 78-50-2
toxicity was noted for animals of both sexes at 300 and 1,000 mg/kg
bw/day. This was supported by changes in clinical pathology endpoints
(increase of ALAT, ASAT, ALP, cholesterol and decrease of albumin, total
protein, among others), increased liver weights (relative weights 12%
and 21% higher for males and females at 300 mg/kg bw/day, and 16% and
40% higher for males and females at 1,000 mg/kg bw/day) and
hepatocellular hypertrophy at the microscopic level. Taken together, the
findings at 300 and 1,000 mg/kg bw/day were considered to be adverse.
The statistical significant higher liver weights in females treated at
100 mg/kg bw/day were not accompanied by changes at the enzymatic or
morphological level. Therefore at this low dose level, the change in
liver weight was considered not to be adverse.
addition, adverse findings were noted in the forestomach starting at 100
mg/kg bw/day in females and at 1,000 mg/kg bw/day in males. At 1,000
mg/kg bw/day, the combination of findings (erosion, hyperplasia,
inflammation, edema) may reflect a response to damage of the forestomach
epithelium by the test substance, including an interruption of the
protective forestomach epithelium. Although only one single female was
affected at 100 mg/kg bw/day, findings were considered as possible
adverse in nature. The reason for this was that the edema was mostly
submucosal located (similar as in the 1,000 mg/kg bw/day group), present
at slight degree, and absent in the concurrent control rats.
target organ were the mesenteric lymph nodes starting at 100 mg/kg
bw/day in both sexes. The finding of vacuolation/vacuolar degeneration
of the macrophages was regarded adverse due to the unusual nature, the
unknown mechanism and the degenerative nature of this change. Possible
adverse test substance-related findings were noted in the spleen
(females) at 1,000 mg/kg bw/day consisting of lower organ weight
correlated with decreased hematopoiesis at the microscopic level. While,
there were no corroborative changes in hematology (such as decreased
haemoglobolin and haematocrite, or increased numbers of reticulocytes)
this finding was regarded as possible adverse.
test substance-related findings were noted in the thyroid glands
starting at 300 mg/kg bw/day in both sexes. The noted increased
incidence and severity of follicular cell hypertrophy may reflect an
increase in thyroxin production in response to feedback mechanisms as a
result of increased turnover of thyroxin by hypertrophic hepatocytes.
The lower thymus weight observed in females at 1,000 mg/kg bw/day with
correlating atrophy at the microscopic level was considered to be
secondary to stress caused by the treatment with the test substance.
treatment-related toxicologically significant changes were noted in any
of the remaining parental parameters investigated in this study (i.e.
clinical appearance, functional observations, haematology, macroscopic
was conducted to assess the reproductive toxicity of the test substance
following repeated administration according to OECD Guideline 422, in
compliance with GLP. Based on the results of a 10 d dose range finding
study, male and female SPFbred Wistar Han rats received dose levels of
100, 300 and 1,000 mg/kg bw/day through oral gavage. One control group
and three treated groups were tested, each consisting of 10 males and 10
females. Males were exposed for 29 d, i.e. 2 weeks prior to mating,
during mating, and up to termination. Females were exposed for 40-47 d,
i.e. during 2 weeks prior to mating, during mating, during post-coitum,
and during at least 4 d of lactation. The following observations and
examinations were evaluated: mortality / viability, clinical signs
(daily), functional observations and locomotor activity (end of
treatment), body weight and food consumption (at least at weekly
intervals), clinical pathology (end of treatment), macroscopy at
termination, organ weights and histopathology on a selection of tissues,
and reproduction/developmental parameters, consisting of mating,
fertility and conception indices, pre-coital time, number of corpora
lutea and implantation sites, gestation index and duration, parturition,
maternal care, sex ratio and early postnatal pup development (mortality,
clinical signs, body weights and macroscopy). No reproduction toxicity
was observed up to the highest dose level tested (1,000 mg/kg bw/day).
No treatment-related toxicologically significant changes were noted in
any of the following reproductive parameters investigated in this study
i.e. mating, fertility and conception indices, pre-coital time, and
numbers of corpora lutea and implantation sites, spermatogenic
profiling, and histopathological examination of reproductive organs. An
increase in postnatal loss and a correspondingly lower viability index
were seen for females at 1,000 mg/kg bw/day. The number of pups that
were found dead or missing during lactation was 5(3) and 17(3) pups
(litter) in the control and 1,000 mg/kg bw/day groups. In the high dose
group, the majority of the pups came from two litters: 6/11 pups in one
litter were missing on Day 3 and all 10 pups in another litter were
found dead or missing on Day 2. Pups missing were most likely
cannibalised. In addition, 3/5 remaining pups in the first litter that
survived until scheduled necropsy had a developmental delay (lean
appearance). Many of these dead pups had no milk in their stomach. No
abnormalities were seen in the mammary glands of the dams. There were no
signs of ill health in other pups from this high dose level. No pups
died or went missing in the 100 and 300 mg/kg bw/day groups. However,
lower body weights of pups were recorded at 1,000 mg/kg bw/day on Days 1
and 4 of lactation. No effects on body weights of pups were noted at 100
and 300 mg/kg bw/day. No treatment-related changes were noted in any of
the remaining developmental parameters investigated in this study i.e.
gestation index and duration, parturition, and maternal care, clinical
signs and macroscopic abnormalities for pups surviving until scheduled
necropsy. Based on the above information, the reproduction NOAEL was
established at 1,000 mg/kg bw/day, while developmental NOAEL was
established at 300 mg/kg bw/day based on the findings of increased post
natal loss and lower pup body weights seen at 1,000 mg/kg bw/day only
(Peter B, 2015)
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