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EC number: 213-234-5
CAS number: 931-36-2
A parental, reproduction, and developmental NOAEL of 150 mg/kg/day (the
highest dose tested) was determined in a GLP compliant, OECD 422,
combined 28 day repeated dose toxicity study with
reproduction/developmental toxicity screening test. Furthermore, no
effects on reproductive organs were observed in a 90 -day study (oral,
rat) up to the highest dose of 230 mg/kg bw/d tested.
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/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/d. 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.
Furthermore, no effects on reproductive organs were observed in a 90
-day study (oral, rat) up to the highest dose of 230 mg/kg bw/d tested
(see IUCLID chapter 7.5.1 for further details).
A prenatal developmental NOAEL of 230 mg/kg/day (the highest dose tested) was determined in a GLP compliant, OECD 414 toxicity test.
2-Ethyl-4-Methyl-Imidazole was tested
for its prenatal developmental toxicity in Wistar rats (2016). The test
substance was administered as an aqueous preparation to groups of 25
time-mated female Wistar rats by gavage at doses of 25, 80 and 230 mg/kg
bw/d on GD 6 through 19. One control group, consisting of 25 females,
was dosed with the vehicle (deionized water) in parallel. A standard
dose volume of 10 mL/kg body weight was used for each test group. At
terminal sacrifice on GD 20, 24 - 25 females per group had implantation
sites. Food consumption and body weights of the animals were recorded
regularly throughout the study period. The state of health of the
animals was checked each day. On GD 20, all females were sacrificed by
decapitation (under isoflurane anesthesia) and assessed by gross
pathology (including weight determinations of the unopened uterus and
the placentae). For each dam, corpora lutea were counted and number and
distribution of implantation sites (differentiated between resorptions,
live and dead fetuses) were determined. The fetuses were removed from
the uterus, sexed, weighed and further investigated for external
findings. Thereafter, one half of the fetuses of each litter were
examined for soft tissue findings and the remaining fetuses for skeletal
(inclusive cartilage) findings. The stability of the test substance
preparations was demonstrated over a period of 7 days at room
temperature. The correctness of the prepared concentrations was shown.
The following test substance-related, adverse effects/findings were
noted at test group 3 (230 mg/kg bw/d):Dams;Statistically significantly
reduced food consumption from GD 6-13, overall about 12% less food
consumption during treatment period (GD 6-19).Body weight statistically
significantly reduced from GD 8-20. Reduced body weight change on GD
6-10, overall about 12% less weight gain during treatment period (GD
6-19). Reduced corrected (net) body weight gain: about 14% below the
concurrent control value.No test substance-related adverse effects on
fetuses. No test
substance-related adverse effects on dams, gestational parameters or
fetuses were seen at test group (80 mg/kg bw/d) and test group 1 (25
mg/kg bw/d). Under
the conditions of this prenatal developmental toxicity study, the oral
administration of 2-Ethyl-4-Methyl-Imidazole to pregnant Wistar rats
from implantation to one day prior to the expected day of parturition
(GD 6-19) at doses as high as 230 mg/kg bw/d caused evidence of maternal
but no developmental toxicity. In
conclusion, the no observed adverse effect level (NOAEL) for maternal
toxicity is 80 mg/kg bw/d based on reduced food consumption and body
weight gain at the LOAEL (230 mg/kg bw/d).The no observed adverse effect
level (NOAEL) for prenatal developmental toxicity is 230 mg/kg bw/d, the
highest dose tested.
Based on the
available data, the test substance does not need to be classified for
reproduction toxicity 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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