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EC number: 203-919-7 | CAS number: 111-90-0
- 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:
- September 2001 to June 2002
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP study conducted under a guideline equivalent protocol
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2002
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- other: ICH S5(R2) Detection of toxicity to reproduction for medicinal products & toxicity to male fertility
- Deviations:
- no
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Principles of method if other than guideline:
- not applicable
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 2-(2-ethoxyethoxy)ethanol
- EC Number:
- 203-919-7
- EC Name:
- 2-(2-ethoxyethoxy)ethanol
- Cas Number:
- 111-90-0
- Molecular formula:
- C6H14O3
- IUPAC Name:
- 2-(2-ethoxyethoxy)ethan-1-ol
- Details on test material:
- - Name of test material (as cited in study report):Transcutol HP; Diethylene glycol mono ethyl ether
- Physical state:Clear colourless liquid
- Analytical purity:99.98%
- Lot/batch No.:D 4089
- Storage condition of test material:at approximately +4C, protected from light and under nitrogen.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source:Iffa Credo, Bp 0109, 69592 l'Arbresle Cedex, France
- Age at study initiation:10-13 weeks old
- Weight at study initiation:199.4-264.5g
- Fasting period before study:none
- Housing:individually hosed in plastic cages with autoclaved sawdust as bedding
- Diet (e.g. ad libitum):ad libitum, pelleted commercial complete rodent diet (Diet reference A04 C-10)
- Water (e.g. ad libitum):ad libitum, mains
- Acclimation period: 6 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C):22+/-2
- Humidity (%):55+/-15
- Air changes (per hr):minimum 15
- Photoperiod (hrs dark / hrs light):12/12
IN-LIFE DATES: From: October 8, 2001 To: October 25, 2001
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: the test article was prepared daily as a solution in the vehicle at the concentrations of 150 and 500mg/ml
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Duplicate 5 ml samples were taken from the formulations (including control) on the first day of treatment and on one day during the last week of treatment. One sample of each formulation was immediately analysed by gas chromatography and the second samples were kept frozen in the event of re-analysis.
- Details on mating procedure:
- - Impregnation procedure: purchased timed pregnant. Animals were received at the testing facility on day 0 of gestation.
- Duration of treatment / exposure:
- From day 6 to day 17 of gestation inclusive
- Frequency of treatment:
- Once daily
- Duration of test:
- Animals were killed on day 20 of gestation
Doses / concentrationsopen allclose all
- Dose / conc.:
- 300 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- Dose / conc.:
- 2 000 mg/kg bw/day
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: dose levels were based on the results of another study (number 935/107)
- Rationale for animal assignment (if not random):random
- Other: Volume of administration: 4ml/kg/day (control and high dose groups) or 2 mg/kg/day (low and intermediate dose groups).
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule:twice daily at the beginning and at the end of each working day (including weekends) to detect any which were dead or moribund.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily. During the treatment period, the animals were observed once before and at least once after the treatment to detect any abnormalities in appearance, behaviour or other signs of reaction to treatment.
BODY WEIGHT: Yes
- Time schedule for examinations: animals were individualy weighed on days 0, 6, 11, 15, 18 and 20 of gestation.
FOOD CONSUMPTION : Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal/day: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Organs examined: Yes. Animals were dissected and examined for macroscopic pathological changes in maternal organs. Any abnormalities observed were recorded and preserved in 10% neutral formalin for possible histopathological examinations. No further examinations were performed.
OTHER: - Ovaries and uterine content:
- For each female, the ovaries and uterus were removed and examined, including examination of the placentae. Uterus and ovaries were not weighed.
The following data were recorded:
pregnancy status
number of corpora lutea
number and distribution of live fetuses
number and distribution of embryonic/fetal deaths
individual fetal weights
fetal sex
The embryonic/fetal deaths were classified as:
early: only placenta visible at termination
late: both placenta and embryonic tissue visible at termination
The uterus of all females was placed in ammonium sulphide solution in order to stain any previously undetected implantation sites. - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter. Following maceration of the soft tissues with aqueuous potassium hydroxide, staining of the skeleton with Alizarin red then passage into glycerol
- Head examinations: Yes
The remaining fetuses were preserved in Harrisson's fluid for fixed visceral examination by the modified Wilson-Barrow technique. Fixed-fetal examinations were performed under low power magnification. - Statistics:
- Data was checked for homogeneity of variance across groups using Bartlett's test. Homogenous data were then analysed by parametric methods, i.e. ANOVA followed by Dunnett's test if ANOVA was significant. Non-homogenous data, were analysed by non-parametric methods, i.e. Kruskal-Wallis test followed by Dunn's test if the Kruskal-Wallis was significant. The numbers of resorptions and all litter-based percentages were analysed using the above non-parametric methods.
Selected incidence data were analysed using a chi2 test for all groups followed by Fisher's two-tailed test with Bonferroni correction for each treated group versus the control if the chi2 was significant. - Indices:
- Pre-implantation loss (in %) = [(Number of corpora lutea - Number of implantations)/Number of corpora lutea]x100
Post-implantation loss (in %) = [(Number of implantations - Number of viable fetuses)/Number of implantations]x100 - Historical control data:
- no data
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
There were no unscheduled deaths throughout the study. There were no treatment-related clinical signs in any group during the study. The body weight gain and mean food consumption during the first five days of treatment (days 6 to 11 of gestation) was statistically significantly lower in comparison with the control group. There were no adverse effect of treatment on mean body weight or mean food consumption for the other treated groups. No treatment-related lesions were found at necropsy examination of the dams.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- 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:
There were at least 24 pregnant females at term in all groups. One dam given 1000mg/kg/day had a single early resorption and no live fetuses. The mean number of uterine implantation as slightly lower in the 300mg/kg/day group due to an incidental increase in pre-implantation loss. Pre-implantation data were comparable in the other treated and control groups. There were no adverse influences of treatment on embryo-fetal survival. Mean fetal weights and sex ratio were comparable in all groups. There were no fetal malformations in any group. There was, however, a dose-related increase in the incidence of fetuses with reduced ossification, principally of the cranial bones, in the 1000 and 2000mg/kg/day groups. None of these reached statistical significance however until the 2000mg/kg dose group.
Effect levels (fetuses)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: embryotoxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: embryotoxicity
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Percentage fetal incidence of selected skeletal abnormalities of potential note.
|
Historical data |
Control |
300mg/kg |
1000mg/kg |
2000mg/kg |
Incomplete ossification of: |
|
|
|
|
|
Cranium – interperietal |
11.6 |
5.5 |
10.7 |
19.3 |
36.4** |
Cranium – supraoccipital |
11.8 |
7.5 |
17.2 |
17.2 |
25.3* |
Cranium – parietal |
3.7 |
0.7 |
0.8 |
4.1 |
11.7* |
Facial – squamosal |
1.3 |
1.4 |
1.6 |
3.4 |
7.1 |
Mandibular: hyoid |
0.6 |
0.7 |
2.5 |
3.4 |
15.6** |
Vertebrae: thoracic 9-13th |
38.0(1) |
22.6 |
25.4 |
31.7 |
43.5 |
Vertebrae: thoracic 1-4th |
38.0(1) |
5.5 |
20.5 |
9.0 |
27.9 |
No ossification of: |
|
|
|
|
|
Mandibular: hyoid |
2.5 |
0.0 |
1.6 |
0.7 |
9.1** |
Other findings |
|
|
|
|
|
Sternebrae: asymmetric |
0.4 |
0.7 |
4.1 |
2.1 |
6.5* |
Number of ribs = 13/14 |
0.7 |
602 |
6.6 |
11.7 |
13.6 |
Number of ribs = 14/14 |
0.3 |
5.5 |
4.1 |
11.7 |
11.7 |
Vertebrae, cervical: advanced ossification of centrum |
15.7 |
61.0 |
36.9 |
27.6 |
11.7* |
(1) recorded for the thoracic vertebrae as one unit
* P<0.05
** P<0.01
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this study a NOAEL was determined at 1000mg/kg/day for maternal toxicity and 300mg/kg/day for embryotoxicity based on dose related observations but 1000mg/kg based on statistical evaluation.
- Executive summary:
In this developmental toxicity study in rats conducted under ICH guidelines, 2 -(2 -ethoxyethoxy)ethanol was administered by gavage from day 6 to day 17 of gestation inclusive at dose levels of 0, 300, 1000, or 2000mg/kg/day. Animals were killed on day 20 of gestation for examination of their uterine contents including examination of the placentae. The high dose level of 2 -(2 -ethoxyethoxy)ethanol resulted in slight maternal toxicity characterised by reductions in body weight gain and food consumption. Evidence of embryo-fetal toxicity was restricted to minor skeletal findings which principally included a dose-related increase in the incidence of reduced ossification of cranial bones in the 1000 and 2000mg/kg/day groups, which were not considered to be indicative of a teratogenic potential of 2 -(2 -ethoxyethoxy)ethanol. Therefore, under the conditions of this study a NOAEL could be determined at 1000mg/kg/day for maternal toxicity and 300mg/kg/day for embryotoxicity based on dose related observations but 1000mg/kg based on statistical evaluation.
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