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EC number: 251-459-0
CAS number: 33329-35-0
The NOAEL for fertility is set at 100 mg/kg bw/day.
No abnormality was attributable to the test item at the low dose group.
Microscopic examination of the high dose and intermediate group animals revealed test item related minimal to moderate centrilobular and/or arterial vacuolation in liver; minimal to moderate arterial vacuolation and /or minimal to mild vacuolation of glomerular tuft in kidneys; minimal to mild arterial vacuolation in urinary bladder; minimal to marked vacuolation of arteries, trabeculae, red and/or white pulp in spleen; minimal to mild arterial vacuolation in thymus; minimal to moderate arterial and/or cortical vacuolation in axillary and/or mesenteric lymph nodes; minimal to moderate vacuolation of arteries, bronchiolar epithelium and/or muscularis in lungs; minimal to moderate epithelial vacuolation in trachea; minimal to moderate vacuolation of vasavasorum, aorta and/or pulmonary artery in heart; minimal to moderate arterial and/or exocrine vacuolation in pancreas; mild to moderate vacuolation of tunica muscularis, arterial and/or parietal layer of stomach; minimal to mild arterial vacuolation in skeletal muscle; minimal to marked vacuolation and necrosis of choroid plexus in brain in both sexes, whereas mild arterial vacuolation in testes and/or epididymides of male animals and minimal to mild arterial vacuolation in ovaries of female animals.
Microscopic examination of high satellite group animals revealed test item related minimal to moderate centrilobular vacuolation, necrosis and/or fibrosis in liver; minimal to mild arterial vacuolation and/or minimal to mild vacuolation to glomerular tuft in kidneys; minimal to moderate arterial vacuolation and /or epithelial vacuolation in urinary bladder; minimal to marked vacuolation of arteries, trabeculae, red and/or white pulp in spleen; minimal to mild arterial and/or cortical vacuolation in axillary and/or mesenteric lymph nodes; mild to marked vacuolation of arteries, bronchiolar epithelium and/or muscularis in lungs; minimal to moderate epithelial vacuolation in trachea; minimal to mild vacuolation of vasavasorum, aorta and/or pulmonary artery in heart; minimal to marked arterial and7or exocrine vacuolation in pancreas; minimal to marked vacuolation of tunica muscularis, arterial and/or parietal layer of stomach; minimal to mild arterial vacuolation in skeletal muscle; mild to marked vacuolation of choroid plexus in brain in both sexes, mild arterial vacuolation in tests of male animals and minimal to mild arterial vacuolation in ovaries of female animals.
However, the lesions observed in high dose satellite group did not reverse after recovery period and seems to be more severe.
Additionally, male and female animals from control and high dose groups and target organs from low dose, intermediate dose and recovery dose group animals showed lesions such as minimal o mild individual cell necrosis, lymphocytic infiltration and/or sinusoidal dilation in liver; minimal to mild necrosis, basophilic tubules, vacuolation of tubular epithelium, tubular dilatation and/or proteinaceous material in kidneys; minimal to mild lymphocytic infiltration, alveolar histiocytosis, haemorrhages and/or presence of keratinized cyst in lungs; minimal to mild vacuolation: dilatation and/or presence of accessory adrenocortical tissue in adrenals; minimal to mild lymphoid necrosis in axillary lymph node; minimal lymphoid necrosis in spleen; minimal to mild necrosis or apoptotic necrosis in pancreas; minimal to apoptotic necrosis in thymus and presence of ectopic thymus or ultimobranchial cyst in thyroid in both sexes and mild oligospermia in epididymis of male animals.
The histopathological examination of organs showing macroscopic findings revealed mild sinusoidal dilatation in liver and mild congestion of stomach, minimal tubular hypertrophy of kidneys, moderate atrophy of tests, azoospermia and/or necrotic debris in epididymides and mild atrophy of seminal vesicles and prostate in one male animal of low dose group, whereas mild polymorphonuclear cells infiltration and luminal dilatation of uterus in one female animal of low dose group and two female animals of high dose satellite group.
The changes observed other than the test item lesions in various tissues during evaluation of control, low, intermediate, high dose and satellite dose group animals were comparable and hence considered incidental. These changes observed can usually be considered to be species, age, gender, congenital, physiological or mode of death related and are covered in background data of pathology.
Short description of key information:
In a combined Repeat Dose Toxicity Study With Reproduction / Developmental Toxicity Screening Test (according to OECD TG 422 and US EPA Health Effects Test Guideline OCSPP (Office of chemical safety and pollution prevention) 870.3650 2000 and under GLP conditions) with structural related N-[3-dimethylamino)propyl]-N,N´,N´-trimethylpropane-1,3-diamine, CAS 3855-32-1, the systemic toxicity and potential adverse effects of the test item on reproduction (including offspring development) were investigated in rats.
The test item (formulated in distilled water) was administered by gavage to three groups of rats (10 males and 10 females for each group) for up to 42 days for males up to two weeks premating phase, two weeks pairing, three weeks gestation and early lactation for females, at dose levels of 50, 100 and 200 mg/kg/day. A control group of 10 males and ten females were dosed with vehicle control. In addition, ten males and 10 females were doses were allocated to satellite group to represent recovery groups for control, and high dose.
Satellite group were treated along with main group animals and dosing was stopped on the day of the first dam sacrifice. Satellite animals were then observed for a further 14-day treatment-free period.
Males were sacrificed on Day 43, followed by the sacrifice for all females on Day 5 post-partum. Pups were sacrificed on Day 4 postpartum.
No mortality was observed in the study. The oral administration of the test substance resulted in treatment-related clinical signs, changes in the body weights, feed consumption and microscopic effects in male and female animals treated with 100 mg/kg/day and 200 mg/kg/day. No toxicologically significant effects were detected in both sex treated with 50 mg/kg day. The vacuolation detected in the various organs of high dose and intermediate dose group were considered to be treatment related and no recovery of microscopic changes where noted in the satellite group. Thus, the “No Observed Adverse Effect Level” (NOAEL) for reproductive toxicity is considered to be 200 mg/kg/day.
Furthermore, 28 and 90-day repeated dose studies conducted with the substance object of registration did not show any adverse effects on the reproductive organ of both genders.
Justification for selection of Effect on fertility via oral route:This study was performed according to OECD Guidelines (No. 422/GLP) and is considered of good quality.
The NOAEL for maternal and developmental toxicity is set at 150 mg/kg bw/day.
Justification for selection of Effect on fertility via oral route:This study was performed according to OECD Guidelines (No. 414/GLP) and is considered of good quality.
Results in Tabular form about effects level on Maternal animals and fetuses are available under in the "Attached background material" under "Overall Remarks"
Justification for selection of Effect on developmental toxicity: via oral route:This study was performed according to OECD Guidelines (No. 414, GLP) and is considered of good quality.
The effect of the substance N,N-bis[3-(dimethylamino)propyl]-N’,N’-dimethylpropane-1,3-diamine, CAS 33329-35-0, was investigated after oral administration in female rats during pregnancy and embryo-foetal development. Animals were administered during gestation period, with 37.5, 75 and 150 mg/kg bw/day, starting from Day 3 through Day 19 post coitum at the dosing volumes of 10 mL/kg.
There were no unscheduled deaths during the study. Pregnancy status: There were 25/25, 25/25, 24/25 and 25/25 pregnant females in control, 37.5, 75 and 150 mg/kg/day.
All pregnant females had viable fetuses. No treatment-related clinical signs were recorded. No significant changes in body weight or body weight gain were seen between groups throughout the study. Food consumption was comparable between groups. No differences between control and treated animals were recorded. Body wight at termination, uterus weight and the absolute weight gain of females were unaffected by treatment.
Relevant reproduction data (corpora lutea, number of implantation sites, pre-and post-implantation losses and number of fetuses at termination) did not indicated any test item-relate effect. Litter and mean foetal weights (combined or by sex) of treated groups were similar to the control and therefore were not considered to be affected by the treatment with the test item. No test item-related effects on the sex ration of the fetuses were noted at any dose level. No changes were seen in anogenital distance between control and treated groups. No relevant changes were observed in the absolute and relative thyroid weight of treated females, when compared to the control data. Females that completed the treatment period did not show relevant macroscopic changes that could be considered treatment-related. No treatment-related findings were noted at the microscopic evaluation of the thyroid gland of the treated females, when compared to their controls. External observations of the fetuses did not reveal any remarkable findings which could be related to treatment. Visceral examinations did not reveal teratogenic potential of the test substance up to and including the dose level of 150 mg/kg bw day.
No treatment-related findings were recorded at skeletal examination of fetuses.
Based on the results obtained in the study, the NOAEL for maternal and developmental toxicity could be set at 150 mg/kg bw/day.
Based on the available data on toxicity to reproduction and development do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.
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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