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EC number: 231-272-0
CAS number: 7473-98-5
OECD 408 study (Repeated Dose Oral
Toxicity 90 days study) conducted to recognised training guidelines with
Repeated dose toxicity study (28 days)
conducted to generally recognised scientific standards.
In this guideline (OECD 408) study
conducted with GLP certification, the repeat dose toxicity NOAEL of the
test material (EC 231-272-0) was determined to be 50 mg/kg bw/day. The
test was conducted in rats, with dose levels of 50, 150 and 400 mg/kg
bw/day. Non-adverse changes (clinical observations, clinical chemistry,
urinalysis, organ weights and histopathology) were observed, primarily
in the highest dosage group.
In this study conducted generally accepted
scientific standards, the repeat dose toxicity NOAEL of the test
material (EC 231-272-0) was determined to be 300 mg/kg bw/day. The test
was conducted in rats, with dose levels of 30, 100, 300, and 1000 mg/kg
bw/day. Increased liver weight was observed in the ≥ 300 mg/kg bw/day
groups, as well as more significant liver changes at 1000 mg/kg bw/day,
especially in females. Thus the liver is considered a target organ for
the test substance.
after repeated dose administration was examined in a subacute 28d study
and in a subchronic 90d study.
the test item was administered orally by gavage to groups of 3 male and
3 female Wistar rats at dose levels of 0 mg/kg body weight/day, 30, 100
mg/kg bw/d, 300 mg/kg bw/d and 1000 mg/kg bw/d for 28 consecuitive days.
A clinical observation (daily) was performed in all animals. Body
weights and food consumption were determined once or twice a week,
respectively. A limited set of selected organs was examined macros- and
microscopically. Increase in liver weight
at doses ≥300 mg/kg/day in both sexes were observed as well as kidney
weight increases in females at 1000 mg/kg/day and hepatocellular
hypertrophy and peripheral liver cell proliferation at 1000 mg/kg/day,
especially in females.
In a second study, rats (10/sex/dose) were
administered to the substance for 90d at concentrations of 50, 150 and
400 mg/kg bw (BASF 2014). All animals were periodically checked for
mortality, clinical signs, body weight gain and food consumption. An
FOB, analysis of blood and urine were also performed. Organ weighing and
gross necropsy was done in all treatment groups, histopathological
examination for control and high dose group only. Transient salivation
and slight transient gait ataxia (males) were observed in high dose
animals. At the end of the study in male and female rats of test group 3
(400 mg/kg bw/d) cholesterol and calcium levels were increased.
Additionally, calcium oxalate and crystals of unknown origin were found
in the urine sediment. An increase in relative and absolute kidney (high
dose) and liver weight (mid and high dose) in males and females was
recorded. Centrilobular hypertrophy correlating to the observed weight
increase was seen in all male and female animals of the high dose group
with grading. In the kidney of top dose males an increased severity of
basophilic tubules was observed, accompanied by granular casts. These
findings were also present in test group 2 (granular cast and slight
In preparation for a teratogenicity study
in rabbits, a dose range finding studies with non-pregnant rabbits was
performed (BASF 2016). In this study, the same clinical symptoms as in
rats were observed. Rabbits were sacrificed in extremis after a single
dose of 500 mg/kg bw. The lower dose group of 150 mg/kg bw was tolerated
with clinical symptoms. No effects were observed at 50 mg/kg bw.
The slight transient gait ataxia in high
dose males immediately after the administration was seen as
treatment-related and adverse. Furthermore, basophilic tubules in
conjunction with granular casts in the mid and high dose group (150 and
400 mg/kg bw) were considered to be adverse. An accumulation of alpha 2u
protein was excluded by special staining and therefore does not explain
the observed findings. Although there was no histopathological
correlate, the weight increase of kidneys of female animals of test
group 3 (400 mg/kg bw) was regarded to be treatment - related and
The NOAEL is considered to be 50 mg/kg bw.
Justification for selection of
repeated dose toxicity via oral route - systemic effects endpoint:
most sensitive study for this endpoint
Repeated dose toxicity: via oral route - systemic effects (target
organ) digestive: liver
Labeling, and Packaging Regulation (EC) No. 1272/2008
available experimental test data are reliable and suitable for
classification purposes under Regulation 1272/2008. Effects observed are
not indicative of serious effects at a dose level of 100 mg/kg for
subchronic exposure. As a result the substance is not considered to be
classified for repeated dose toxicity under Regulation (EC) No.
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