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EC number: 500-062-3 | CAS number: 28390-91-2
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- 4,4'-methylenebis[N,N-bis(2,3-epoxypropyl)aniline] is methylenebisbenzenamine with four epoxy groups and is considered as a monoconstituent substance under REACH with a purity > 80% and containing the following impurities: triglycidyl-(2-hydroxy-3-chloropropyl)-methylenedianiline in a range of 3.5 to 4%, dimeric TGMDA in a range of 3 to 5%, triglycidyl-(2,3-dihydroxypropyl)-methylenedianiline in a range of 0.3 to 1%, triglycidyl-(2-hydroxypiperidine)-methylenediamine in a range of 0.5 to 1%, triglycidyl methylenedianiline in a range of 0.3 to 0.8%, (2-hydroxy-3-chloropropyl)-dimeric TGMDA in a range of 0.2 to 0.6%, and trimeric TGMDA in a range of 0.2 to 0.5%. The hypothesis is to read-across some data from the monoconstituent substance described above to the corresponding UVCB substance as described under REACH. The UVCB substance being chemically similar and just differ from the monoconstituent substance by the purity of the main constituent which is < 80% but still stay in the same order of magnitude. The impurities from the monoconstituent substance being also present in the same order of magnitude in the UVCB substance containing also two additional substances, 2-oxiranemethanamine, %{N}-[4-[[4-[[3-chloro-2-(oxiranylmethoxy)propyl](oxiranylmethyl)amino]phenyl]methyl]phenyl]-%{N}-(oxiranylmethyl)- in a range of 0.5 to 2 % and less than 1% 1-[(4-{4-[bis(oxiran-2-ylmethyl)amino]benzyl}phenyl)(oxiran-2-ylmethyl)amino]-3-[(4-{4-[(3-chloro-2-hydroxypropyl)(oxiran-2-ylmethyl)amino]benzyl}phenyl)(oxiran-2-ylmethyl)amino]propan-2-ol. The main assumption is that the minor differences in terms of percentage between the mono and UVCB substance are not significant in respect of all properties under consideration. The full report on read-across approach is attached in section 13 of the IUCLID file.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes
Test material
- Test material form:
- liquid: viscous
- Details on test material:
- Name : 4,4’-methylenebis[N,N-bis(2,3-epoxypropyl)aniline]
Q4E and ERC Nr.12
All denominations correspond to the same test item.
. Purity : 84.9%
. Description : high viscous yellow to brown liquid
. Container : 2 containers
. Storage condition : at +2-8°C
. Correction factor : 1.18
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- Animals:
-Number: 96 time-mated females rats were received at CiToxLAB France between 28 November and 18 December 2012.
-Strain and sanitary status: Sprague-Dawley, Crl CD® (SD) IGS BR, Caesarian Obtained, Barrier
Sustained-Virus Antibody Free, (COBS-VAF®).Breeder: Charles River Laboratories Italia, Calco, Italy.
-Age/Weight: at the beginning of the treatmen period, the animals were 10-11 weeks old and had a mean body weight of 273 g(223 g to 323 g). The females were sexually mature and primigravid.
-Mating: Females were mated at the breeder's facilities.
Environmental conditions:
-Temperature: 22 +/- 2°C.
-Relative humidity: 50 +/- 20%.
-Light/dark cycle: 12h/12h.
-Ventilation: about 12 cycles/hour of filtered, non-recycled air.
Housing.
-The animals were individually housed in polycarbonate cages (Techniplast 2154, 940 cm2) with stainless steel lids and containing autoclaved sawdust (SICSA, Alfortville, France). Individual housing was chosen because of software limitations and since it is preferable for pregnant animals. Each cages containes enrichment (rat hut).
Food and water.
-All animals had free access to SSNIFF R/M-H pelleted maintenance diet, batch N° 2537604 (SSNIFF Spezialdiäten GmbH, Soest, Germany) which was distributed weekly. The animals had free access to bottles containing tap water (filtered with a 0.22 microm. filter).
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Remarks:
- PEG 400 batch N° MKBG6036V
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): The dose formulations were administred daily from day 6 to day 20 p.c., inclusive.
VEHICLE
-Vehicle (if other than water):The vehicle was PEG 400.
- Lot/batch no. (if required):N° MKBG6036V.
- Amount of vehicle (if gavage): 5 ml/kg/day - Analytical verification of doses or concentrations:
- yes
- Details on mating procedure:
- The females were mated at the breeder's facilities. The day of confirmed mating (detection of a vaginal plug) was designated as a day 0 p.c.
- Duration of treatment / exposure:
- 15 days.
- Frequency of treatment:
- Daily
- Duration of test:
- Females were sacrified on day 20 p.c.
- No. of animals per sex per dose:
- Group 1: 24 time-mated females, dose level: 0 mg/kg/day, concentration: 0 mg/ml.
Group 2: 24 time-mated females, dose level: 30 mg/kg/day, concentration: 6 mg/ml.
Group 3: 24 time-mated females, dose level: 90 mg/kg/day, concentration: 18 mg/ml.
Group 4: 24 time-mated females, dose level: 270 mg/kg/day, concentration: 54 mg/ml. - Control animals:
- yes
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS:
- Time schedule: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:Daily
BODY WEIGHT: Yes
- Time schedule for examinations: day 2, 4 ,6, 9, 12, 15, 18 and 21 p.c., and priormto premature sacrifice.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
The quantity of food consumed by each female was recorded for the following intervals: days2-4, 4-6, 6-9, 9-12, 12-15, 15-18 and 18-21 p.c..
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined:
-Thoracic and abdominal organs
-The ovaries and uterus: All organs examined macroscopically
uterus - live and dead fetuses, resorption sites, placentas
ovaries - corpora lutea
OTHER:
- The weight of the gravid uterus was recorded
- placenta weights
- for apparently non-pregnant females the presence of implantation scars on the uterus was checked using the ammonium sulphide staining technique.
- presence of iron in uterus walls with ammonium sulphide to detect invisible implantation sites - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Number and distribution of dead and live fetuses, number and distribution of uterine scars. - Fetal examinations:
- - External examinations: Yes
Each fetus (excluding the autolyzed fetus) was subjected to a detailed external examination, which included the observation of all visible structures, surfaces and orificies.
- Soft tissue examinations: Yes: half per litter.
- Skeletal examinations: Yes: all per litter - Statistics:
- - All data are recorded and calculated using computerized validated software (Reprotox version B.1).
- Data of non-pregnant females are not included in group mean calculations such as body weight, body weight change, food consumption and litter data. - Indices:
- No data.
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 90 mg/kg bw/day
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 90 mg/kg bw/day
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
At 270 mg/kg/day, mean feta body weight and mean placenta weight were lower than in controls which correlated with the effect seen on mean gravid uterus. when compared with controls, the differences were statistically significant and considered to be adverse.
There were no effects on mean fetal body weight at 30 and 90 mg/kg/day and on mean fetal/placenta weight ratio at any dose-level.
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Maternal NOAEL: 90mg/kg/day
Fetal NOAEL: 90 mg/kg/day - Executive summary:
The test item, 4,4’-methylenebis[N,N-bis(2,3-epoxypropyl)aniline] (batch No. AAB0290400), was administered by gavage, once daily, from days 6 to 20 p.c., inclusive, to time-mated female Sprague-Dawley rats at dosages of 30, 90 or 270 mg/kg/day. On the basis of the results obtained in this study: . the No Observed Adverse Effect Level (NOAEL) for maternal parameters was considered to be 90 mg/kg/day based on the premature death, adverse clinical signs and effects on mean body weight and mean body weight change (including carcass and net body weight) and mean food consumption at 270 mg/kg/day, . the NOAEL for embryo-fetal development was considered to be 90 mg/kg/day based on increased litter and fetal incidence of delayed/absent bone ossification and of malformations at 270 mg/kg/day in a context of severe maternal toxicity.
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.
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