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EC number: 213-234-5
CAS number: 931-36-2
A NOAEL of 80 mg/kg bw/d was determined in a GLP compliant OECD 408
90-day oral toxicity study. In a GLP compliant, OECD 422, combined 28
day repeated dose toxicity study with reproduction/developmental
toxicity screening test a NOAEL of 150 mg/kg bw/d was determined.
administered by gavage to groups of 10 male and 10 female Wistar rats at
dose levels of 0, 25, 80 and 230 mg/kg bw/d over a period of 3 months
(2016). Food consumption and body
weight were determined weekly. The animals were examined
for signs of toxicity or mortality at least once a day. In
addition, the rats were daily examined for any clinically abnormal signs
before and within 2 hours as well as within 5 hours after treatment. Detailed
clinical examinations in an open field were conducted prior to the start
of the administration period and weekly there after.Ophthalmological
examinations were performed before the beginning and at the end of the
administration period. Beside this, a functional observational battery
(FOB) as well as measurement of motor activity (MA) were carried out at
the end of the administration period. Clinicochemical and hematological
examinations as well as urinalyses were performed towards the end of the
administration period. After the administration period all animals were
sacrificed and assessed by gross pathology. Organ weights were
determined followed by histopathological examinations. The
following test substance-related, adverse findings were noted in the HD
group (230 mg/kg bw/d). Clinical examinations showed decreased body
weight in males from study day 56 onwards (up to -10.1% on study day
84), decreased body weight in females on study day 84 only (-6.1%),
decrease body weight gain in males from study day 49 onwards (up to -16%
between study day 0 and 84; -14.5% between study day 0 and 91) and
decreased body weight gain in females on study day 84 only (-11.0%;
-5.9% between study day 0 and 91, non-statistically significant).
Clinical chemistry showed increased total white blood cell (WBC) and
absolute neutrophil counts in males, increased urea, cholesterol and
inorganic phosphate levels in both sexes, decreased chloride levels in
both sexes, increased triglyceride levels in females and decreased
albumin levels in females. Pathology showed decreased terminal body
weight in both sexes (-11% in males and -5% in females), increased mean
absolute and relative liver weights in females and minimal centrilobular
hepatocellular hypertrophy in 9/10 female animals(in combination with
clinical chemistry). No treatment-related, adverse effects were observed
at doses of 80 mg/kg bw/d and 25 mg/kg bw/d. The
administration of 2-Ethyl-4-Methyl-Imidazole by gavage to
male and female Wistar rats for 3 months caused signs of systemic
toxicity at a dose level of 230 mg/kg bw/d. Therefore, under the
conditions of the present study the no observed adverse effect level
(NOAEL) was 80 mg/kg bw/d for male and female Wistar rats.
In a GLP compliant combined 28 -days
repeated dose toxicity study with reproduction/developmental toxicity
screening test, 2 -ethyl-4 -methylimidazole was given to rats by oral
gavage (2012). Four groups of ten male and ten female Wistar Han rats
were exposed to the test substance at 15, 50, or 150 mg/kg bw/d. Rats of
the control group received the vehicle, water, alone. Males were exposed
for 29 days, i.e. 2 weeks prior to mating, during mating, and up to
termination. Females were exposed for 43-56 days, i.e. during 2 weeks
prior to mating, during mating, during postcoitum, and during at least 4
days of lactation. Accuracy, homogeneity and stability of formulations
were demonstrated by analyses. Locomotor activity as determined by total
movements and ambulations were comparable in all groups (both sexes).
Mean values remained within the normal range of biological variation.
All groups showed a comparable habituation profile with high activity in
the first interval that decreased over the duration of the test period.
Lower levels of total protein and albumin at 150 mg/kg bw/d were noted
for females, and higher liver weights (absolute and relative to body
weight) were recorded at 15, 50 and 150 mg/kg bw/d for males. These
changes were minor or occurred in the absence of a dose-related trend,
means were within the range considered normal and/or histopathological
support was absent. Therefore, these changes were not considered to be
toxicologically relevant. No test substance related findings were noted
in any of the other parameters investigated in this study (mortality /
viability, clinical signs, functional observations other than for
locomotor activity, body weight, food consumption, haematology,
macroscopy, organ weights and histopathology). There were 9, 10, 7 and 8
litters available for evaluation in the control, 15, 50 or 150 mg/kg
bw/d groups, respectively. No morphological findings were noted in the
reproductive organs of the animals that failed to sire or deliver
healthy pups. Moreover, there was no dose-dependency, and the sizes of
the litters were within normal ranges up to 150 mg/kg bw/day. Therefore,
the lower numbers of pregnant females in Groups 3 and 4 were considered
to be a chance finding. The seven litters available for evaluation in
the 50 mg/kg bw/d group was slightly lower than the advised minimum of
eight litters as mentioned in the guideline. Nevertheless, sufficient
data could be obtained from the remaining litters of this group and the
other groups for an accurate evaluation of possible developmental
effects. In conclusion, no reproduction and developmental toxicity was
observed up to the highest dose level tested (150 mg/kg bw/d). Based on
these results, a parental, reproduction and developmental NOAEL of at
least 150 mg/kg bw/d was derived.
Based on the
NOAEL of 80 mg/kg/bw and the LOAEL of 230 mg/kg bw/d, observed in the
oral repeated dose toxicity study, the test substance does not need to
be classified according to the EU Classification, Labelling and
Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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