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EC number: 201-304-8 | CAS number: 80-73-9
28-day repeated dose toxicity (HRC, 1989)
28-day repeated dose toxicity NOAEL(oral) = 30 mg/kg bw/day
28-day repeated dose toxicity (Biosafety researc Centre, 2011)
28-day repeated dose toxicity NOAEL(oral) = 20 mg/kg bw/day
The repeated dose toxicity of the test material was investigated in a GLP study which was conducted accoding to a methodology similar to the standardised guideline OECD 407.
During the study, groups of rats received DMI, formulated as a solution, at dose levels of 6, 30 and 150 mg/kg bw/day, daily, for a period of 28 consecutive days, by oral gavage. Clinical findings, bodyweight changes, food consumption, haematology parameters, biochemistry parameters and urinalayses were conducted throughout the study. Following treatment on day 28, the animals were sacrificed. Organs were weighed and macroscopic and microscopic pathology investigation ensued.
Under the conditions of the study, the No Observed Adverse Effect Level (NOAEL) of DMI for the males was judged to be 30 mg/kg/day each in the conditions of this study because of the effects on the testis and epididymis of the150 mg/kg group.
The repeated dose toxicity of the substance was investigated in a study which was conducted under GLP conditions and in accordance with the standardised guideline OECD 422.
During the study the test material was administered at 0 (treated with the solvent, water for injection, only), 4, 20 or 100 mg/kg/day by gavage to rats from 14 days prior to mating to the end of the 14-day mating period. Males were further dosed for 14 days from the end of the mating period. Daily dosing of the parental females continued throughout pregnancy and up to day 4 of lactation period. Five males from the main groups and an additional 5 females (satellite groups) were used for the observation of reversibility for 14 days post treatment.
Parameters evaluated included clinical signs, bodyweight changes, food consumption, urinanalysis, blood biochemistry, haematology, functional observational battery examination. Following sacrifice, organ weights were recorded gross pathology and histopathology examinations were carried out.
Under the conditions of the study no males or females were dead or moribund. The given test material did not affect the general conditions, including the detailed observation in the FOB.
During the dosing period, gains in the body weight were lower or tended to be lower in the males and females of the 100 mg/kg group. However, the body weight gains were higher during the recovery period. Therefore, the given test material showed a tendency to reduce the body weight gain and a tendency to recovery of the weight gain by the withdrawal was seen.
As an effect on the food consumption, the mean daily food consumption of female 100 mg/kg group was lower during the lactation period.
In the haematological examination of the female 100 mg/kg group, haematocrit, haemoglobin and red blood cell count were higher and reticulocyte ratio tended to be lower on day 5 of lactation.
In the blood chemical examination of the male 100 mg/kg group, triglyceride and total cholesterol were higher or tended to be higher. Moreover, total protein was lower in the female 100 mg/kg group on day 5 of lactation.
In the serum protein electrophoresis of the female 100 mg/kg group on day 5 of lactation, the concentrations and ratios of albumin and gamma-globulin fractions and A/G ratio were lower, and the ratio of beta-globulin fraction was higher.
Pathological examination revealed a macroscopical change as atrophy of testis and epididymis in the male 100 mg/kg group. Also, the weights of these organs were lower in the same group. These changes are considered to be caused by the dosing of test substance. As the histopathological findings, atrophy and vacuolation of seminiferous tubule, multinucleated giant cell formation and interstitial cell hyperplasia were observed in testis in the male 100 mg/kg group. In addition, at the end of the recovery period, Sertoli cell-only syndrome (the finding which shows that most reproductive cells disappeared and only Sertoli cells remain in the seminiferous tubule) was found in the testis. At the end of the dosing period, decrease of sperm and cell debris in the lumen were found in the epididymis. At the end of the recovery period, decrease of sperm was found in the epididymis. In females, the spleen weight was lower in the 100 mg/kg group. However, no histopathological changes which were considered to be caused by the dosing of test material were found.
Therefore, under the conditions of the study, the No Observed Adverse Effect Level was considered to be 20 mg/kg bw/day
28-day repeated dosie toxicity (HRC, 1989)
The registered substance does not meet the criteria for classification for Specific Target Organ Toxicity - Repeated Exposure (STOT-RE) according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.
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