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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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 25 January 2007 to 11 October 2007
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: A well reported GLP study conducted under a guideline equivalent protocol.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 007
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)
- Deviations:
- no
- 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
- Physical state: clear, colorless liquid
- Analytical purity: 100%
- Lot/batch No.: 450449013; 450449013
- Storage condition of test material: Room temperature, under nitrogen
Constituent 1
Test animals
- Species:
- dog
- Strain:
- Beagle
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Ridglan Farms, Inc., Mt. Horeb, Wisconsin
- Age at study initiation: 5-6 months old
- Weight at study initiation: males - 6.3 to 9.1kg; females - 5.3 to 7.9kg
- Fasting period before study: overnight prior to blood collection for serum chemistry and prior to necropsy.
- Housing: Individually in stainless steel cages elevated above stainless steel cage pans. Animals were allowed regular opportunity for exercise and social interaction in accordance with the standard operating procedures.
- Diet : Offered once daily. Approximately 400g of PMI Nutrition International, LLC, Certified Canine LabDiet 5007. On dosing days feed bowls from the previous day were removed approximately 1 hour prior to dosing and new feed was offered after the 2-hour post-dosing clinical observations. In addition, at the discretion of the study director, the daily diet of individual animals was supplemented appropriately with Alpo or Science Diet A/D to maintain the health status of the animals.
- Water : ad libitum, mains water.
- Acclimation period: at least 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20+/-3
- Humidity (%): 50+/-20
- Air changes (per hr): minimum 10
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 2007, February 5 To: 2007 May 8
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Group 2 - 400mg/kg/day - test article concentration: 80mg/ml
Group 3 - 1000mg/kg/day - test article concentration 200mg/ml
Group 4 - 2000/1500mg/kg/day - test article concentration 400/300mg/ml
The test article formulations were prepared approximately weekly as single formulations for each dosage level, divided into aliquots for daily dispensation and stored refrigerated, protected from light, under nitrogen. The pH was measured: On 2 February 2007, the pH measurements for the 80, 200 and 400mg/ml formulations were 9.09, 9.16 and 9.47, respectively. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Two sets of duplicate samples for concentration analysis were collected from the study week 0, 3, 6, 9 and 12 formulations at the time of preparation from each dosing formulation (including the vehicle formulation administered to the control group). The analyses were conducted by gas chromatography.
- Duration of treatment / exposure:
- 91 days
- Frequency of treatment:
- continuous
Doses / concentrations
- Remarks:
- Doses / Concentrations:
400, 1000, 1500 and 2000 mg/kg/day
Basis:
other: gavage, 5ml/kg
- No. of animals per sex per dose:
- Control, and 1500/ 2000mg/kg/day groups: 6 males and 6 females
400 and 1000mg/kg/day groups: 4 males and 4 females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Dose levels were selected based on the results of a previously conducted escalating and 7-day repeat dose range-finding study (WIL-261016; Padgett, 2007).
Initial dosages were 400, 1000 and 2000 mg/kg/day for groups 2-4, respectively. However, within approximately the first 2 weeks of dose administration, individual dogs in the 2000mg/kg/day group were noted with dose-limiting toxicity. Subsequently, the high dose was lowered from 2000mg/kg/day to 1500mg/kg/day. Dose administration was suspended for the 2000mg/kg/day group from study days 16 to 20 (males) and 15 to 19 (females). Dose administration at 1500mg/kg/day resumed on study day 21 for the remaining males and study day 20 for remaining females. - Positive control:
- not applicable
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily except on nondosing days during dose suspension for animals in the 2000mg/kg/day group, when it was once daily.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly, beginning approximately 2 weeks prior to test article administration and prior to the scheduled necropsy.
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to the initiation of dose administration (Week -1) and near the end of the treatment period (Week 13).
- Dose groups that were examined: all animals
HAEMATOLOGY: Yes
- Time schedule for collection of blood: From all dogs, prior to the initiation of dose administration (Week -1) and the day of the scheduled necropsy (Week 13)
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes, overnight
- How many animals: All
- Parameters checked in table No. 1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: From all dogs, prior to the initiation of dose administration (Week -1) and the day of the scheduled necropsy (Week 13)
- Animals fasted: Yes, overnight
- How many animals: All
- Parameters checked in table No. 2 were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: From all dogs, prior to the initiation of dose administration (Week -1) and the day of the scheduled necropsy (Week 13)
- Metabolism cages used for collection of urine: Yes, for an approximate 24-hour period
- Animals fasted: No
- Parameters checked in table No.3 were examined.
NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:
OTHER:
TOXICOKINETICS:
Blood samples were collected at 0.5, 1, 2, 4, 8 and 24 hours after dose administration on study days 0 and 86.
Urine samples were collected for an approximate 24-hour period overnight on study days 0 and 86.
ELECTROCARDIOGRAPHIC DATA:
Multilead ECGs were recorded for all animals prior to the initiation of dose administration (Week -2) and during study week 12 using the Multi Lead ECG equipment with the Ponemah platform from LDS Test and Meaurements, LLC. During the treatment period, ECGs were recorded approximately 2 hours after dose administration. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes in all animals. The necropsies included, but were not limited to, examination of the external surface, all orifices, and the cranial, thoracic, abdominal and pelvic cavities including viscera. The following organs were weighed from all animals at the scheduled necropsy: Adrenals, brain, heart, kidneys, liver, ovaries, pituitary, prostrate, spleen, testes, thymus, thyroid with parathyroids, uterus with cervix.
HISTOPATHOLOGY: Yes (see table 4) - Other examinations:
- no data
- Statistics:
- Analyses were conducted using two-tailed tests (except as noted otherwise) for minimum significance levels of 1% and 5%, comparing each test article-treated group to the control group by sex. Statistical analyses were not conducted if the number of animals was <=2.
Body weight, body weight change, food consumption, clinical pathology, heart rate and organ weight data were subjected to a parametric one-way analysis of variance (ANOVA) to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunnett's test was used to compare the test article-treated groups to the control group.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- effects observed, treatment-related
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
Following 6 and 12 consecutive days of dose administration, 2 males and 1 female, respectively, in the 2000mg/kg/day group were euthanised in extremis on study days 7 and 15. These three animals showed clinical findings (hypoactivity, diarrhea and emesis), a marked decrease in food consumption, as well as pronouced body weight losses. The most probably cause of morbidity, based on histologic findings was moderate to severe renal tubular degeneration.
All other animals survived to the scheduled necropsy. There were no test substance-related clinical observations in the 400 or 1000mg/kg/day groups and no test substance-related clincial observations noted for the remaining animals in the 1500mg/kg/day group.
BODY WEIGHT AND WEIGHT GAIN
Body weight effects were noted in the 1000mg/kg/day female group, 2000mg/kg/day group, and the 2000/1500mg/kg/day female group.
Body weights in the 400mg/kg/day group, 1000mg/kg/day group males and 2000/1500mg/kg/day group males were generally similar to the control group values throughout the dose administration.
FOOD CONSUMPTION
Test substance-related effects on food consumption were noted for the 2000mg/kg/day group males and females.
OPHTHALMOSCOPIC EXAMINATION
No effect observed.
HAEMATOLOGY, CLINICAL CHEMISTRY and URINALYSIS
Slight, non-adverse differences from controls in hematology (MCV and MCH), serum chemistry (alkaline phosphatase, albumin, A/G ratio, chloride, bicarbonate) and urine chemistry (specific gravity, osmolality, pH and electrolyte balance) parameters were noted in the 400, 1000 and/or 2000/1500mg/kg/day groups at week 13. These differences from controls were relatively small and may represent the residual effects of a regenerative response in the case of the red blood indices or compensatory/adaptive mechanisms in the case of slightly elevated alkaline phosphatase and/or differences in urine parameters to eliminate the test article.
ORGAN WEIGHTS
Higher liver weights were noted in the 1000mg/kg/day group females and the 2000/1500mg/kg/day group males and females at the scheduled necropsy. The slightly higher liver weights for these groups may be associated with the somewhat elevated alkaline phosphatase serum levels observed for these groups at the study week 13 clinical chemistry evaluations. There were no histologic correlates related to the increase in liver weights. The liver weight differences from control may be a reflection of an adaptive response related to the metabolism of the test article and the differences from control were not considered adverse.
GROSS PATHOLOGY
Gross necropsy observations findings in the animals euthanized in extremis included pale kidneys in the males; enlarged kidneys with reddened cortico-medullary junction in the female; dark red areas in the esophagus, stomach, duodenum and/or ileum for both sexes, and reddened mucosa and or intussusception in the ileum for both sexes. Microscopic correlates for these observations were renal tubular degeneration int he kidney; ulceration or erosion in the esophagus, stomach and duodenum and hemorrhage and muscle degeneration in the ileum.
HISTOPATHOLOGY: NON-NEOPLASTIC
There were no test substance-related organ-specific microscopic findings of consequence at any dosage level for the animals surviving to the scheduled necropsy, and the histologic alterations in the unscheduled death animals associated with dosage at 2000mg/kg/day were considered reversible, since there was no histologic evidence of injury in the animals continued to be dosed at 1500mg/kg/day.
OTHER FINDINGS
No test substance-related effects were noted in the electrocariographic data at the study week 12 evaluation.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: This is the highest dosage level administered for the entire duration of the study and it corresponds to plasma levels of 3159-6346ug*h/ml.
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Analytical chemistry: the analysed dosing formulations were found to contain the amount of test article prescribed in the protocol (90 -110% of target concentration) with a few exceptions that the study director deemed not to be significant.
Table 5. Mean toxicokinetic results for DEGEE
Plasma |
% of Dose eliminated in urine over 24 hours |
|||||
|
Oral Dosage (mg/kg/day) |
AUC (ug*h/ml) |
Cmax (ug/ml) |
Tmax (h) |
T1/2 (h) |
|
Males |
||||||
Day 0 |
400 |
875 |
434 |
0.50 |
0.94 |
0.31 |
1000 |
4088 |
1280 |
0.63 |
0.89 |
5.2 |
|
2000/1500 |
12890 |
2516 |
1.1 |
2.1 |
4.3 |
|
Day 86 |
400 |
1366 |
504 |
0.63 |
1.2 |
0.73 |
1000 |
6346 |
1443 |
0.50 |
1.7 |
1.8y |
|
2000/1500 |
10479yy |
2248yy |
0.63yy |
2.1yy |
2.9yy |
|
Females |
||||||
Day 0 |
400 |
904 |
434 |
0.63 |
0.89 |
0.50 |
1000 |
3159 |
1124 |
0.63 |
0.80 |
1.4 |
|
2000/1500 |
10756 |
2501 |
0.75 |
1.6 |
3.5 |
|
Day 86 |
400 |
958 |
469 |
0.50 |
1.0 |
0.6 |
1000 |
5195 |
1421 |
0.50 |
1.1 |
2.4 |
|
2000/1500 |
8877# |
2093# |
0.50# |
1.5# |
2.4# |
|
N=4 at 400 and 1000mg/kg/day; N=6 at 2000/1500mg/kg/day, exceptyN=3;yy=N=4; #N=5 |
||||||
*AUC = AUC0-inf on Day 0, or AUC0-24 on Day 86 |
Table 6. Mean toxicokinetic results for EEAA
Plasma |
% of Dose eliminated in urine over 24 hours |
|||||
|
Oral Dosage (mg/kg/day) |
AUC (ug*h/ml) |
Cmax (ug/ml) |
Tmax (h) |
T1/2 (h) |
|
Males |
||||||
Day 0 |
400 |
1396 |
301 |
2.0 |
1.4 |
31 |
1000 |
5628 |
667 |
4.0 |
1.9 |
45 |
|
2000/1500 |
13276 |
983 |
6.7 |
2.2 |
57 |
|
Day 86 |
400 |
2140 |
345 |
4.0 |
2.0 |
45 |
1000 |
6952 |
632 |
4.0 |
1.9 |
52y |
|
2000/1500 |
9602yy |
789yy |
4.0yy |
2.2yy |
41yy |
|
Females |
||||||
Day 0 |
400 |
1944 |
339 |
2.0 |
2.0 |
53 |
1000 |
4782 |
620 |
3.5 |
1.9 |
49 |
|
2000/1500 |
12059 |
972 |
4.0 |
2.2 |
50 |
|
Day 86 |
400 |
2031 |
347 |
2.5 |
2.1 |
44 |
1000 |
6201 |
787 |
4.0 |
1.8 |
57 |
|
2000/1500 |
8143# |
730# |
4.0# |
1.9# |
47# |
|
N=4 at 400 and 1000mg/kg/day; N=6 at 2000/1500mg/kg/day, exceptyN=3;yy=N=4; #N=5 |
||||||
*AUC = AUC0-inf on Day 0, or AUC0-24 on Day 86 |
Applicant's summary and conclusion
- Conclusions:
- A NOAEL of 1000mg/kg/day can be concluded from this study
- Executive summary:
In a GLP 13 -week study in male and female dogs, 2 -(2 -ethoxyethoxy)ethanol was administered at 400, 1000, or 2000mg/kg/day by oral gavage. A fourth control group was given the vehicle water. Based on the results of this study, the initial high dose of 2000mg/kg/day was not well tolerated as evidenced by clinical findings, pronounced body weight losses and decreased food consumption which resulted in mortality for 2 males and 1 female within the first 2 weeks of dose administration. The primary histologic alteration contributing to the morbidity for these dogs was severe renal tubular degeneration in the kidney. The dosage level was subsequently lowered to 1500mg/kg/day for the remaining animals. Slight, non-adverse differences from controls in hematology, serum chemistry and urine chemistry parameters were noted in the 400, 1000 and/or 2000/1500mg/kg/day groups. Higher liver weights were observed in the 1000mg/kg/day female group and the 2000/1500mg/kg/day group at the scheduled necropsy, which may be associated with the slightly elevated srum ALP levels resulting from an adpative response related to the metabolism of the test article. There were no organ-specific microscopic findings of consequence at any dosage level for the animals surviving to the scheduled necropsy, and the histologic alterations in the unscheduled death animals associated with dosage at 2000mg/kg/day were considered reversible, since there was no histologic evidence of injury in the animals continued to be dosed at 1500mg/kg/day. The 1500mg/kg/day dose was well tolerated. Based on the results of this study the NOAEL was considered to be 1000mg/kg/day (3159 -6346 ug*h/ml) for both male and female dogs.
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