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EC number: 700-584-3 | CAS number: 1217271-02-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- from 2014-09-10 to 2014-11-04
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 015
- Report date:
- 2015
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- 1996
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- [2,2-dimethyl-3-(morpholin-4-yl)propylidene][(5-{[2,2-dimethyl-3-(morpholin-4-yl)propylidene]amino}-1,3,3-trimethylcyclohexyl)methyl]amine
- EC Number:
- 700-584-3
- Cas Number:
- 1217271-02-7
- Molecular formula:
- C28H52N4O2
- IUPAC Name:
- [2,2-dimethyl-3-(morpholin-4-yl)propylidene][(5-{[2,2-dimethyl-3-(morpholin-4-yl)propylidene]amino}-1,3,3-trimethylcyclohexyl)methyl]amine
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Toxi-Coop Zrt., Cserkesz u. 90., H-1103 Budapest, Hungary
- Age at study initiation: Male animals: 83 – 87 days old, Female animals: 83 – 87 days old
- Weight at study initiation: Male animals: 330 – 399 g, Female animals: 205 – 252 g. The weight variation in animals involved at the starting point of the study did not exceed ± 20 % of the mean group weight of each sex.
- Housing: Before mating: 2 animals of the same sex/ cage, Mating hours: 1 male and 1 female / cage, Pregnant females were housed individually. Males after mating: 2 animals / cage.
- Diet: ssniff® SM R/M-Z+H "Autoclavable complete feed for rats and mice – breeding and maintenance, ad libitum
- Water: ad libitum
- Acclimation period: 20 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Remarks:
- PEG 400
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Formulations were prepared in the formulation laboratory of the Test Facility beforehand not longer than for 24 hours before use.
VEHICLE
- Justification for use and choice of vehicle: The test item is not soluble in water therefore PEG 400 was used for preparing formulations appropriate for oral administration. PEG 400 was shown to be a suitable vehicle to facilitate formulation analysis for the test item. The same vehicle was used previously for very similar substances with good results. Sufficient historical control data with this vehicle are available.
- Concentration in vehicle: The test item was formulated in the vehicle in concentrations of 200, 60 and 20 mg/mL. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Recovery of the test item from PEG 400 formulations was measured using a reverse phase HPLC method with UV detection on a BDS Hypersil C18 column (150x4.6 mm 3 μm). Analysis of formulations (checking of concentration and homogeneity) was performed in the Analytical Laboratory of Test Facility two times during the study. Five samples (5 mL, each) were taken from different places from each concentration (Groups 2, 3 and 4) and all samples were measured. Similarly, five samples (5 mL, each) were taken from the vehicle (Group 1), from different places, and analyzed.
- Duration of treatment / exposure:
- Female animals were dosed for 14 days pre-mating, during mating period, through gestation and up to lactation days 3 - 11 (altogether for 48 or 55 days depending on day of mating).
- Frequency of treatment:
- daily
- Details on study schedule:
- - Age at mating of the mated animals in the study: about 14 weeks
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- Remarks:
- Basis: actual ingested
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Remarks:
- Basis: actual ingested
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Remarks:
- Basis: actual ingested
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose setting based on findings obtained in a previous repeated dose oral gavage toxicity study with Sika Hardener MI in rats and after consultation of the Sponsor (Toxi-Coop study no. 644-400-0050). In general, the doses were selected with the aim of inducing toxic effects but no death or suffering at the highest dose and a NOAEL at the lowest dose.
- Positive control:
- none
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: Parent male animals were weighed on the first day of dosing (Day 0), weekly thereafter and on the day of necropsy.
Parent females were weighed on the first day of dosing (Day 0) then weekly, on gestation days 0, 7, 14 and 21 and on post-partum day 0 (within 24 hours after parturition) and post-partum days 4 and 7, if it was feasible.
FOOD CONSUMPTION AND COMPOUND INTAKE:
- The food consumption was determined weekly by reweighing the non-consumed diet with an accuracy of 1 g during the treatment period except mating days (pre-mating and post mating for male animals and non-pregnant females, during pre-mating, gestation days 0, 7, 14 and 21, lactation days 0, 4 and 7 for dams; latter if was feasible). - Oestrous cyclicity (parental animals):
- not examined
- Sperm parameters (parental animals):
- Parameters examined in male parental generations:
Percentage of pairings, percentage of fertile pairings, percentage of infertile pairings, male copulatory index, male fertility index were calculated.
Testes, epididymides (total and cauda), prostate, and seminal vesicles with coagulating glands were preserved.
Testis weight and epididymis weight of all parental animals were determined. - Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
PARAMETERS EXAMINED
The following parameters were examined in offspring:
sex ratio, survival index of pups on postnatal day 4, Number of live births per litter, and number of viable pups per litter on postnatal days 0 and 4, Mean body weight gain per litter between postnatal days 0-4, Litter weight on postnatal days 0 and 4.
Lung flotation test was performed on offspring found dead on postnatal day 0.
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals one day after the last treatment.
- Maternal animals: All surviving animals one day after the last treatment.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Tables 1 and 2 were prepared for microscopic examination and weighed, respectively. - Postmortem examinations (offspring):
- SACRIFICE
Offspring euthanized on day 4 post-partum, were carefully examined for gross abnormalities externally.
GROSS NECROPSY
- Gross necropsy consisted of macroscopic examinations including the cervical, thoracic, and abdominal viscera, a lung flotation test was performed. - Statistics:
- The homogeneity of variance between groups was checked by Bartlett’s homogeneity of variance test.
Where no significant heterogeneity was detected a one-way analysis of variance (ANOVA) was carried out. If the obtained result was significant Duncan Multiple Range test was used to access the significance of inter-group differences. Getting significant result at Bartlett’s test the Kruskal-Wallis analysis of variance was used and the inter-group comparisons were performed using Mann-Whitney U-test. Chi2 test was performed if feasible.
The frequency of clinical signs, pathology and histopathology findings were calculated.
Results were evaluated in comparison with values of control group (i.e. control value). - Reproductive indices:
- Copulatory Indices, Fertility Indices, Gestation Indices were determined.
- Offspring viability indices:
- Pre-implantation mortality, Post-implantation mortality, Intra uterine mortality, Post-natal mortality, Sex ratio and Survival Index were calculated.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There was no test item related mortality in parental animals during the course of study at any dose level. Adverse signs of systemic toxicity related to the test item were not detected at any dose level at the daily clinical observations.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- No test item related mortality was observed.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- The body weight development was not affected.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- There were no test item or treatment related changes in the food consumption of male and female animals at any dose level.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- The test item did not cause any toxic or other test item related lesions detectable by histological examination in the genital and other organs of the experimental animals.
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- The various spermatogenic cells (the spermatogonia, the spermatocytes, the spermatids and spermatozoa), representing different phases in the development and differentiation of the spermatozoons and the interstitial cells were the same in quantity and morphologically in the testes of investigated control and treated animals.
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- The examined parameters of reproductive performance were not affected by the treatment with the test item at 1000, 300 or 100 mg/kg bw/day in male or female animals.
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed.
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- The percentage of cold offspring was slightly higher than in the control group at 1000 mg/kg bw/day on postnatal day 0. However, this finding was not considered to be toxicologically relevant as it was transient and of low incidence. Moreover, this observation was not associated with any influence on the development of the offspring.
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- There was no test item related effect on pup’s mortality.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- A test item effect on the body weight development of the offspring was not found.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- Test item related clinical signs were not detected in the offspring.
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Test item related macroscopic alterations were not found in offspring subjected to gross pathological examination.
- Histopathological findings:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- Sex Distribution:
There were no test item related differences between the control and test item treated groups in the ration or in the litter means of genders on postnatal days 0 or 4.
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effect observed.
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- not specified
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The test item did not adversely influence the reproductive performance (gonad function, mating behavior, conception, pregnancy, parturition) in parental male and female Hsd.Brl.Han: Wistar rats. The development of the F1 offspring from conception to day 4 post-partum, after repeated oral administration of the dams, was not impaired at any dose level. Based on these observations the No Observed Adverse Effect Levels (NOAEL) for reproductive performance of male/female rats and for F1 Offspring was 1000 mg/kg bw/day.
- Executive summary:
Four groups of Hsd.Brl.Han: Wistar rats (n=12/sex/group) were administered with the test item orally (by gavage) once a day at 0 (vehicle), 1000, 300 and 100 mg/kg bw/day corresponding to concentrations of 0, 200, 60 and 20 mg/mL. The application volume was 5 mL/kg bw. Control animals received the vehicle, Polyethylene glycol 400 (PEG 400). All animals of the parent (P) generation were dosed prior to mating (14 days) and throughout mating. Females were additionally exposed through the gestation period and up to lactation days 3 -11, i.e. up to the day before necropsy (altogether for 48 or 55 days). Observations included mortality, clinical signs, body weight, food consumption, mating, pregnancy and delivery process, as well as development of offspring. Each five dams and the male mating partners were randomly selected from each group to examine further signs of toxicity such as functional observations, hematology, clinical chemistry, gross necropsy, organ weighing and histopathology. The dams were allowed to litter, and rear their offspring up to day 4 post-partum. Litters were weighed and offspring were observed for possible abnormalities and were euthanized on postnatal day 4. All parental animals were subjected to gross pathology one day after the last treatment. Histopathology examination was performed on reproductive organs (testes, epididymides, uterus and ovaries) and pituitary in the control and high dose groups. The reproductive organs and pituitary of non-pregnant females and cohabited males in the low and mid dose groups were also processed and evaluated histopathologically. Additionally, full histopathology was performed on the organs and tissues of animals selected for general toxicological examinations in the control and high dose groups. The results were interpreted comparing treatment groups with respect to controls, which were treated concurrently with vehicle (Polyethylene glycol 400) only. Historical control data were also considered. As a result, there were no test item related differences between the control and test item treated groups in delivery data of dams and in the reproductive performance of male and female animals. No adverse findings on offspring development (mortality, clinical signs, body weight) or at necropsy were detected in the offspring terminated as scheduled. Based on these findings, the NOAEL for reproductive performance of the parental animals and for the development of the offspring was determined to be 1000 mg/kg bw.
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