Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 266-235-8 | CAS number: 66204-44-2
- 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:
- experimental study
- Adequacy of study:
- key study
- Study period:
- December 2005 (Study Plan) to April 02, 2008 (Final Report)
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- Guideline study, well performed according to good scientific standards. On a few test days the relative humidity was outside the range 40-70% (minor restriction)
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 008
- Report date:
- 2004
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 006
- Report date:
- 2006
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 3,3'-methylenebis[5-methyloxazolidine]
- EC Number:
- 266-235-8
- EC Name:
- 3,3'-methylenebis[5-methyloxazolidine]
- Cas Number:
- 66204-44-2
- Molecular formula:
- C9H18N2O2
- IUPAC Name:
- 3,3'-methylenebis[5-methyloxazolidine]
- Details on test material:
- - Name of test material (as cited in study report): N,N'-Methylen-bis-(5-methyloxazolidine) (MBO) (GrotaMar 71)
- Substance type: Formaldehyde releaser
- Physical state: Almost clear, colourless liquid
- Analytical purity: 99%
- Composition of test material, percentage of components: Reaction product from paraformaldehyde and 2 hydroxypropylamine (ratio of 3:2)
- Purity test date: 29. Nov 2005
- Lot/batch No.: 1094394
- Expiration date of the lot/batch: June 2007
- Stability under test conditions: Stability and homogeneity of the test substance in corn oil has been shown
- Storage condition of test material: At room temperature
Constituent 1
Test animals
- Species:
- rabbit
- Strain:
- Himalayan
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: LPT, Branch Facility Löhndorf, 24601 Löhndorf, Germany
- Age at study initiation: 4-5 months
- Weight at study initiation: 2.33-3.24 kg body weight
- Fasting period before study: no
- Housing: Breeding cages with wire floors
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: In-house bred, their state of health was checked prior to the start of the study
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C ± 3°C
- Humidity (%): 55% ± 15%
- Photoperiod: 12 hrs dark / 12 hrs light
IN-LIFE DATES: From December 12, 2005 (first administration) to February 16, 2006 (termination of inlife phase)
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test item was diluted in the vehicle to the appropriate concentrations
VEHICLE
- Justification for use and choice of vehicle (if other than water): The test item is instable in water, formaldehyde will be deceased off. Hence, at
the request of the sponsor, corn oil was employed as vehicle, however, as little as possible.
- Concentration in vehicle: 0, 0.25, 2.25, 4.5, 6.75%
- Amount of vehicle (if gavage): 2 mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The stability and homogeneity of the test substance in corn oil has been measured in an analytical study (Preiß, 2006). Samples collected immediately after preparation of the formulation as well as 8 h after storage were analysed. Homogeneity was examined in samples collected at the start of administration, during administration and before treatment of the last animal. Stability and homogeneity of the test substance in corn oil has been shown.
- Details on mating procedure:
- - Impregnation procedure: Monogamous mating
- M/F ratio per cage: 1/1
- Length of cohabitation: Until successful copulation was observed
- Further matings after unsuccessful attempts: Rabbits lacking signs of copulation were excluded from the analysis
and replaced by additional spare animals.
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: Successful copulation was ascertained by observation (considered as day 0 of pregnancy). - Duration of treatment / exposure:
- Day 6 to 28 of pregnancy
- Frequency of treatment:
- One daily oral gave treatment
- Duration of test:
- Until Day 28 of pregnancy. Sacrifice on Day 29
- No. of animals per sex per dose:
- 24 animals per group at initiation
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: In a preliminary study 2 pregnant rabbits per dose received 20, 60, 180 mg/kg bw/day on day 6-28 of pregnancy in 2 ml/kg bw corn oil. NOEL for effects on foetuses 60 mg/kg bw. Maternal NOEL <20 mg/kg bw/day (slight gastric lesions); lethal effects at 180 mg/kg bw.
- Rationale for animal assignment (if not random): random
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Viability checked twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once daily data were recorded. Dated and signed records of appearance, change and disappearance of clinical
signs were maintained on clinical history sheets for individual animals.
BODY WEIGHT: Yes
- Time schedule for examinations: Determined daily (day 0-29), always at the same time of the day
FOOD CONSUMPTION Yes
- Daily food consumption recorded and relative food consumption calculated (related to body weight)
WATER CONSUMPTION
- Daily monitoring by visual appraisal of the drinking water consumption was maintained
throughout the study
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: In order to check for possible drug effects, a dissection with macroscopic examination
of the internal organs of the dams was carried out on the day of scheduled laparotomy or on the day on which the animals were found dead.
OTHER:
The kidneys (2) of all dams were preserved in 10% buffered formalin for possible future histopathological examination.
In case of macroscopical findings, the affected maternal tissues were preserved in 10% buffered formalin for possible future histopathological examinations. - 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: Weight of placentae - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]: The thorax and peritoneal cavity (without damage to ribs and sternum)
were opened; location, size and condition of the internal organs were determined and examined for abnormalities of soft tissue
- Skeletal examinations: Yes: [all per litter form the eviscerated fetuses (intact and headless bodies)]
- Head examinations: Yes: [half per litter]
- Other: Litter size, no. of dead & alive foetuses, no of placentae, foetal weight measured; sex ratio; and viability after a 6 h and a 24 h stay in the incubator at 34°C determined; foetuses examined for external malformations; thereafter foetuses sacrificed (ether) and dissected; - Statistics:
- For all numerical values, homogeneity of variances was tested using the BARTLETT chi-square test.
When the variances were homogeneous, the DUNNETT test (p ≤ 0.01) was used to compare the experimental groups with the control group.
In case of heterogeneity of variances, the STUDENT's t-test was carried out, limit of significance was p ≤ 0.01.
For the comparison of classification measurements (for example malformation-, resorption-, retardation- and variation rate) the FISHER's exact test (n < 100)
or chi2-test with YATES' correction for continuity (n ≥ 100) (p ≤ 0.05 and p ≤ 0.01) was employed. - Indices:
- Malformation rate [%]
Variation rate [%]
Retardation rate [%]
Pre-implantation loss [%]
Post-implantation loss [%] - Historical control data:
- Yes: Background data available
(summarized results of the 30 last embryotoxicity studies in rabbits (Himalayan) performed at LPT in the years 2000 - 2005)
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- ≤ 90 mg/kg bw/day
these dose levels caused no test substance related clinical effects - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- ≤ 90 mg/kg bw/day
these dose levels caused no test substance related mortality.
135 mg/kg bw/day
increased mortality (10 pregnant rabbits between gestation day 9
and 23 - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- ≤ 90 mg/kg bw/day
No effects
135 mg/kg bw/day
body weight reduced (max. 9%); the body weight change was
significantly reduced at gestation day 9-12, 18-21, and 27-29. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- ≤ 90 mg/kg bw/day
No effects
135 mg/kg bw/day
Treatment related effects on absolute and relative food
consumption; significant at gestation day 11-14 and 28. - Water consumption and compound intake (if drinking water study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- 135 mg/kg bw/day
decrease of gravid uterus weight - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- ≤ 90 mg/kg bw/day:
Soft faeces and gastric lesions were noted in
several animals including controls; this is presumably caused by
the vehicle corn oil (possible confounding factor).
135 mg/kg bw/day
severe gastro-intestinal lesions in prematurely deceased dams
(n=10), in dams with abortion (n=4) and in surviving dams.
Increased incidence of dilatation of the renal pelvis - Histopathological findings: neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- ≤ 90 mg/kg bw/day
No effects
135 mg/kg bw/day
severe gastro-intestinal lesions in prematurely deceased dams
(n=10), Necropsy revealed changes of the kidney (dilatation of renal pelvis).
Maternal developmental toxicity
- Description (incidence and severity):
- ≤ 90 mg/kg bw/day
The abortions in controls and treated groups are within the normal variability
(1-2 per group).These
findings were considered to be within the spontaneous range.
135 mg/kg bw/day
increased abortions - Pre- and post-implantation loss:
- effects observed, treatment-related
- Description (incidence and severity):
- ≤ 90 mg/kg bw/day
Total post implantation loss was noted in one dam at 5 and 90 mg/kg bw/day. These
findings were considered to be within the spontaneous range.
135 mg/kg bw/day
post-implantation loss (n=3) (52.6% versus 13.7% in
control). - Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- ≤ 90 mg/kg bw/day
no effect - Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- ≤ 90 mg/kg bw/day
no effect - Dead fetuses:
- effects observed, treatment-related
- Description (incidence and severity):
- ≤ 90 mg/kg bw/day
no effect
135 mg/kg bw/day
significant increase - Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- ≤ 90 mg/kg bw/day
no effect - Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Malformations
No test substance related findings were recorded at external
examination of foetuses. External malformations were detected in
all groups including control excluding high dose group (but only
5 dams evaluated) and were considered to be of spontaneous
nature. No test substance related macroscopic visible variations
were detected.
Skeletal examination of the foetuses revealed no test substance
related increase in variations, retardations or malformations in
any group. The observed effects were within the spontaneous
range. - Details on maternal toxic effects:
- ≤ 90 mg/kg bw/day
No developmental effects were detected with respect to the
number of corpora lutea (determined values: number per dam,
absolute number per group, mean per group), implantations
(number per dam, distribution in uterine horns, absolute number
per group, mean per group), resorptions (number per dam,
distribution in uterine horns, absolute number per group, mean
per group, mean % per group, early resorptions, late resorptions),
weight of placenta (individual data per foetus, mean per litter,
mean per group, litter mean per group, litter mean per sex and
group), weight of foetuses (individual data per foetus, mean per
litter, mean per sex and litter, litter mean per group, litter mean
per sex and group), foetuses (number of alive or dead per dam,
number per sex and dam, distribution in uterine horns, absolute
number alive per group, mean number alive per group, mean%
alive per group, mean % per sex and group) when compared to
the control. Abortions were found in 1-2 dams per group
including the control (n=2 abortions). Total post implantation
loss was noted in one dam at 5 and 90 mg/kg bw/day. All these
findings were considered to be within the spontaneous range.
135 mg/kg bw/day
Due to the high mortality rate (n=10 dams) and abortions (n=4)
and/or post-implantation lost (n=3) only 5 litters could be
evaluated. The number of early and late resorptions was
increased (p≤0.01), the number of foetuses decreased (p≤0.01)
and the post-implantation loss increased (52.6% versus 13.7% in
control). The mortality of foetuses during the 6-h incubator stay
was significantly increased (9/24; p<0.01).
Effect levels (maternal animals)
- Dose descriptor:
- NOEL
- Effect level:
- >= 90 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
At 135 mg/kg b.w./day, a total post-implantation was noted in 3 of 8 examined dams. The number of early and total resorptions was significantly increased, the number of fetuses accordingly decreased.
At 5, 45, 90 or 135 mg/kg b.w./day, no test item-related malformations or variations were noted during external or skeletal examination of the fetuses
(according to DAWSON) and soft tissue examination of the fetal heads (according to WILSON).
Skeletal examination (according to DAWSON) revealed no test item-related retardations at any tested dose level.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 90 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: fetotoxicity
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Macroscopic findings in the stomach and the kidney of dams at necropsy (at gestation day 29 & prematurely deceased rabbits)
Finding |
Control n=23# |
5 mg/kg bw n=24# |
45 mg/kg bw n=23# |
90 mg/kg bw n=21# |
135 mg/kg bw n=22# |
Stomach |
|
|
|
|
|
Detachment and/or reddening of mucosa |
1# |
2# |
1# |
0 |
10# |
Reddened stomach |
0 |
0 |
3 |
3# |
10# |
Ulcer(s) |
0 |
2# |
1 |
0 |
4# |
Haemorrhagic/dark/ reddish/black foci |
0 |
0 |
1 |
4# |
8# |
Distensions |
0 |
0 |
0 |
0 |
3 |
Any lesion (from individual data, Table A7) |
1/23 |
2/24 |
6/23 |
7/21 |
22/22 |
Duodenum |
|
|
|
|
|
reddened |
0 |
0 |
0 |
0 |
2# |
Kidney |
|
|
|
|
|
Dilatation of renal pelvis |
1 |
4# |
4# |
4 |
12# |
Coarse structure of cortex |
0 |
0 |
2 |
0 |
2# |
Very soft tissue |
0 |
0 |
0 |
0 |
1 |
#: (including) prematurely deceased dams |
Developmental toxicity
Finding |
Control n=20 |
5 mg/kg bw n=21 |
45 mg/kg bw, n=20 |
90 mg/kg bw, n=17 |
135 mg/kg bw, n=8 |
Corpora lutea total |
158 |
166 |
149 |
131 |
63 |
Corpora lutea per dam |
7.9 |
7.9 |
7.5 |
7.7 |
7.9 |
Total implantation sites |
135 |
133 |
128 |
104 |
51 |
Implantation sites/dam |
6.8 |
6.3 |
6.4 |
6.1 |
6.4 |
Total resorptions |
15 |
15 |
12 |
9 |
27** |
Resorptions/dam |
0.8 |
0.7 |
0.6 |
0.5 |
3.4 |
Total early resorptions |
11 |
15 |
11 |
8 |
26** |
Early resorptions/dam |
0.6 |
0.7 |
0.6 |
0.5 |
3.3 |
Total late resorptions |
4 |
0* |
1 |
1 |
1 |
Late resorptions/dam |
0.2 |
0.0 |
0.1 |
0.1 |
0.1 |
Mean% pre-implantation loss |
14.8 |
18.6 |
16.7 |
20.0 |
18.0 |
Mean% post-implantation loss |
13.7 |
10.3 |
9.5 |
10.1 |
52.5 |
Total live foetuses |
120 (n=20) |
118 (n=20) |
116 (n=20) |
95 (n=16) |
24** (n=5) |
Live foetuses per dam |
6.0 |
5.9 |
5.8 |
5.9 |
4.8 |
Total dead foetuses at laparatomy |
0 |
0 |
0 |
0 |
0 |
*: p≤0.05; **: p≤0.01 |
Applicant's summary and conclusion
- Conclusions:
- The test substance has no teratogenic properties. The observed developmental effects occurred only at dose levels inducing severe maternal toxicity.
- Executive summary:
Study according to OECD guideline 414. Prenatal developmental toxicity study of the test substance in rabbits by oral administration. 24 pregnant rabbits per dose were gavaged with 0, 5, 45, 90, 135 mg/kg bw/day (concentration: 0, 0.25, 2.25, 4.5, 6.75% in corn oil) at gestation day 6-28.
Maternal toxicity: At 135 mg/kg bw/day a decrease in body weight, increased mortality and abortions indicated clear maternal toxicity. Necropsy revealed local lesions in the stomach and an increased incidence in dilatation of the renal pelvis.
No effects were found at 90 mg/kg bw/day. The effects in the stomach (see Table above) were related by the authors to the vehicle corn oil. The authors concluded that no test substance related effects were found at 90 mg/kg bw/day.Developmental toxicity: No developmental effects were detected at 90 mg/kg bw/day. At the high dose level the number of early and late resorptions was increased, the number of foetuses decreased, the post-implantation loss and the mortality of foetuses during the 6-h incubator stay increased. No increase in the incidence of retardations, variations or malformations was detected in any treatment group.
In conclusion, the test item N,N'-Methylen-bis-(5-methyloxazolidine) possessed no teratogenic properties. Embryotoxic properties were noted only at severe maternal toxicity at 135 mg/kg b. w./day in form of an increased resorption rate.
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.