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EC number: 272-712-1 | CAS number: 68909-77-3 The residuum from the reaction of diethylene glycol and ammonia. It consists predominantly of morpholine-based derivatives such as [(aminoethoxy)ethyl]morpholine, [(hydroxyethoxy)ethyl]morpholine, 3-morpholinone, and 4,4'-(oxydi-2,1-ethanediyl)bis[morpholine].
- 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:
- 2018-07-27 - 2019-11-15
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- 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:
- Ethanol, 2,2'-oxybis-, reaction products with ammonia, morpholine derivs. residues
- EC Number:
- 272-712-1
- EC Name:
- Ethanol, 2,2'-oxybis-, reaction products with ammonia, morpholine derivs. residues
- Cas Number:
- 68909-77-3
- Molecular formula:
- Not applicable (UVCB)
- IUPAC Name:
- 2-(2-hydroxyethoxy)ethan-1-ol; 2-[1-(morpholin-4-yl)ethoxy]ethan-1-amine; 2-{2-[bis(2-hydroxyethyl)amino]ethoxy}ethan-1-ol; 4-{2-[2-(morpholin-4-yl)ethoxy]ethyl}morpholine; morpholin-3-one
- Test material form:
- liquid
- Details on test material:
- Name: Ethanol, 2,2'-oxybis-, reaction products with ammonia, morpholine derivs. residues
Physical state: liquid
Appearance: brown liquid
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch number of test material: Huntsman Europe BVBA and 17/19961
- Expiration date of the lot/batch: 2019-11-22
- Purity test date: Not applicable (UVCB)
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At ambient temperature (15 to 25°C); protected from light and moisture.
- Stability under storage conditions: Not specified
- Stability under test conditions: Before commencement of treatment, the suitability of the proposed mixing procedures was determined and specimen formulations at 2and 200mg/mL were analyzed to assess the stability of the test item in the liquid matrix.
- Solubility and stability of the test substance in the solvent/dispersant/vehicle/test medium: Not specified
- Reactivity of the test substance with the solvent/vehicle /test medium (if applicable): Not specified
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Mixed to vehicle (purified water)
- Final preparation: The required amount of test item was weighed. Approximately 50% of the final volume of vehicle was added and magnetically stirred until the test material was uniformly mixed. The remaining vehicle was added to achieve the required volume and the formulation was mixed using a magnetic stirrer until homogeneous.
A series of formulations at the required concentrations were prepared in ascending order.
- Frequency of preparation: Weekly, in advance of dose administration.
- Storage of formulation: Refrigerated at 2 to 8°C
OTHER SPECIFICS
- Physical State/appearance: Brown liquid
- other information: No correction factor
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Envigo RMS.
- Age at study initiation (day 0 of gestation): 19 to 23 weeks old
- Weight at study initiation: 2.82 to 4.61 kg
- Fasting period before study: No
- Housing: Suspended cages fitted with perforated floor panels and mounted in batteries. Undertrays lined with absorbent paper were changed at least three times a week. Cages were also fitted with a plastic resting platform.
Number of animals per cage: acclimatization one female, during mating one stock male and one female, during gestation one female.
- Diet (e.g. ad libitum): Teklad 2930 Diet, the diet contained no added antibiotic or other chemotherapeutic or prophylactic agent. Availability was restricted (initially 150g/animal/day during acclimatization up to one week prior to the onset of mating and 200g/animal/day thereafter). Should an individual show a significant non-treatment related reduced food consumption, moistened diet (50 g pelleted diet moistened with 20 to 50 mL of water) was offered and the consumption was recorded. In addition to this diet, a small supplement of autoclaved hay was given on a daily basis to promote gastric motility and a small amount of chopped fresh vegetables were given twice weekly. Consumption of hay and vegetables were monitored qualitatively but not quantitatively.
- Water (e.g. ad libitum): Ad libitum. Potable water from the public supply via polycarbonate bottles with sipper tubes. Bottles were changed at appropriate intervals. Water bowls were offered to individuals during acclimatization.
- Acclimation period: 19 days before commencement of mating.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 15 - 21°C
- Humidity (%): 45 - 70%.
- Air changes (per hr): Filtered fresh air which was passed to atmosphere and not recirculated.
- Photoperiod (hrs dark / hrs light): 10/14
IN-LIFE DATES: From: 2018-07-04 To: 2018-08-24
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
-The test item was prepared at the appropriate concentrations as a solution in Distilled Water.
- The stability of formulations was demonstrated over a period of up to 21 days at 2 to 8°C and one day at ambient temperature (15 to 25°C). Formulations were therefore prepared weekly and stored at approximately 2 to 8 ºC.
VEHICLE
- Justification for use and choice of vehicle (if other than water): not applicable (vehicle is water)
- Concentration in vehicle: 0, 25, 50,100 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg body weight
- Purity: not specified - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The homogeneity and stability was confirmed for Amine C8 in Distilled Water formulations at nominal concentrations of 2 mg/mL and 200 mg/mL when stored refrigerated for 21 days and at room temperature in the light for 24 hours.
Samples of test item formulations were taken on two occasions and analyzed for concentration and the results indicate that the prepared formulations were within 100-112% of the nominal concentration. - Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: 6 days
- Further matings after two unsuccessful attempts: not specified
- Verification of same strain and source of both sexes: not specified
- Proof of pregnancy: Expelled uterine contents were identified and examined, as appropriate
- Any other deviations from standard protocol: No applicable - Duration of treatment / exposure:
- Day 6 to 28 after mating
- Frequency of treatment:
- Once daily at approximately the same time each day.
- Duration of test:
- 29 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Control
- Dose / conc.:
- 125 mg/kg bw/day (nominal)
- Remarks:
- Group 2
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Remarks:
- Group 3
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Remarks:
- Group 4
- No. of animals per sex per dose:
- 22 females per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: not specified
- Rationale for animal assignment (if not random): Where possible only females mating at least twice were allocated.
Method to group and cage position in the sequence of mating: Females mating on any one day were evenly distributed amongst the groups.
Allocation was controlled to prevent any stock male from providing more than one mated female in each treated group and to prevent more than one sibling female in each group, where possible.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked in table were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. A detailed physical examination was performed on each animal on Days 0, 6, 12, 18, 24 and 29 after mating to monitor general health.
BODY WEIGHT: Yes
- Time schedule for examinations: The weight of each adult was recorded weekly during acclimatization, on Days 0, 3 and 6-29 after mating
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- The weight of food supplied to each animal, that remaining and an estimate of any spilled was recorded daily from Day 1 after mating.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
POST-MORTEM EXAMINATIONS: Yes
- All adult animals were subject to a detailed necropsy. After a review of the history of each animal, a full macroscopic examination of the tissues was performed. All external features and orifices were examined visually. Any abnormality in the appearance or size of any organ and tissue (external and cut surface) was recorded and the required tissue samples preserved in appropriate fixative. - 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: Fetuses (live and dead). - Fetal examinations:
- - External examinations: Yes [half per litter]
- Soft tissue examinations: Yes [ half per litter]
- Skeletal examinations: Yes [half per litter]
- Head examinations: Yes: [ half per litter ] - Statistics:
- The following sequence of statistical tests was used for body weight, gravid uterus weight, food consumption, corpora lutea, implantations, pre/post implantation loss, live young, sex ratio - percentage male, placental, litter and fetal weights:
A parametric analysis was performed if Bartlett's test for variance homogeneity (Bartlett 1937) was not significant at the 1% level. For pre-treatment data, analysis of variance was used to test for any group differences. Where this was significant (p<0.05) inter group comparisons using t-tests, with the error mean square from the one-way analysis of variance, were made. For all other analyses the F1 approximate test was applied.
A non-parametric analysis was performed if Bartlett's test was still significant at the 1% level following both logarithmic and square-root transformations. For pre-treatment data, Kruskal-Wallis’ test (Kruskal and Wallis 1952, 1953) was used to test for any group differences. Where this was significant (p<0.05) inter group comparisons using Wilcoxon rank sum tests (Wilcoxon1945) were made. For all other analyses the/The H1 approximate test, the non-parametric equivalent of the F1 test described above, was applied.
Significant differences between the groups compared were expressed at the 5% (p<0.05) or 1% (p<0.01) level.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no signs were observed at either routine physical examination or in association with dose administration that could be related to treatment.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One female dosed at 125 mg/kg/day was euthanized prematurely with evidence of abortion. Uterine examination revealed a single implantation that was resorbing. This was therefore considered to be a resorption rather than abortion and as there was a solely a single implant it is considered to relate to biological efficiency rather than an effect of treatment.
One female dosed at 500 mg/kg/day prematurely delivered six live offspring, one dead offspring and one late resorption within the animal facility. The live offspring were euthanized within the animal facility and dispatched to necropsy for subsequent examinations. Macroscopic examination of female no 72 and offspring did not reveal any findings that could be attributed to treatment. As this was an isolated incidence it was considered to be unrelated to administration of Amine C8. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- As treatment progressed weight gain for females receiving 500 mg/kg/day was low when compared with Controls and overall the bodyweight gain from GD6 to GD29 bodyweight gain was 17% of Controls (p<0.01). The overall body weight gain for females at 125 or 250 mg/kg/day were similar to the Controls and showed no adverse effect of treatment.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- The mean food consumption for females receiving 500 mg/kg/day was slightly but consistently low from Day 6 to Day 27 of gestation when compared with Controls, with the total consumption over the treatment period at approximately 79% of the Control value.
At 250 mg/kg/day there were occasions of slightly low consumption however overall the food consumed was similar to Control values.
Food consumption at 125 mg/kg/day was unaffected by treatment with Amine C8. - 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The maternal body weight loss following adjustment for the gravid uterine weight was slightly greater than Controls for females that received 500 mg/kg/day; however this difference did not attain statistical significance. The maternal weight loss for females at 125 or 250 mg/kg/day were similar to the Controls and showed no adverse effect of treatment.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Macroscopic examination of females did not reveal any findings that could be attributedto treatment with Amine C8.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The post-implantation loss (%) for females at 500mg/kg/day was slightly high when compared with Controls and the resultant mean litter size was low when compared with Controls (p<0.05). However, the live litter size and percentage of post implantation loss were within the historical control data range so no effect of treatment is inferred.
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One control female and 3 females treated at 250 mg/kg/day were found to be not pregnant at macroscopic examination. There was no clear effect of treatment on offspring survival and litter size at 125 or 250 mg/kg/day.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Group mean placental weights, male or fetal weight and overall fetal weight were essentially similar to Controls at dose levels up to and including 500 mg/kg/day.
- Reduction in number of live offspring:
- not examined
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The mean litter weight for females that received 500 mg/kg/day was slightly but significantly low when compared with Controls; this was attributed to the low live litter size rather than the mean fetal weight at this dose level.
- Changes in postnatal survival:
- not examined
- External malformations:
- not specified
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The range and incidence of major abnormalities at 125 and 500 mg/kg/day showed no relationship to treatment. At 500 mg/kg/day there was a slight increased incidence of full supernumerary 13th ribs and unilateral caudal shift of pelvic girdle when compared with both the Concurrent Controls and the historical control data range. The combination of these skeletal variants at 500 mg/kg/day indicates a slight shift in rib/vertebral configuration which is not considered adverse.
- Visceral malformations:
- not examined
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- skeletal malformations
Fetal abnormalities
- Key result
- Abnormalities:
- effects observed, non-treatment-related
Overall developmental toxicity
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 500 mg/kg bw/day (nominal)
- Treatment related:
- no
- Relation to maternal toxicity:
- not specified
- Relevant for humans:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Oral administration of the test substance to New Zealand White rabbits from Day 6 to Day 28 of gestation at dose levels of 125, 250 or 500 mg/kg/day was associated with low maternal body weight gain and food consumption at 500 mg/kg/day.
Embryo-fetal survival, fetal and placental weight were unaffected by treatment and the fetal pathology findings at 500 mg/kg/day were minor skeletal variants which were not considered adverse.
It was therefore concluded that 250 mg/kg/day was the no observed effect level (NOEL) for both maternal toxicity and embryo-fetal development.
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