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EC number: 203-963-7 | CAS number: 112-36-7
- 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: inhalation
Administrative data
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 30 August 2012 - 11 January 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP compliant study conducted in accordance with OECD guidelines.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.8 (Subacute Inhalation Toxicity: 28-Day Study)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
Test material
- Reference substance name:
- Bis(2-ethoxyethyl) ether
- EC Number:
- 203-963-7
- EC Name:
- Bis(2-ethoxyethyl) ether
- Cas Number:
- 112-36-7
- Molecular formula:
- C8 H18 O3
- IUPAC Name:
- 1-ethoxy-2-(2-ethoxyethoxy)ethane
- Reference substance name:
- Diethylene Glycol Diethyl Ether
- IUPAC Name:
- Diethylene Glycol Diethyl Ether
- Test material form:
- not specified
- Details on test material:
- - Name of test material (as cited in study report): Bis(2-ethoxyethyl)ether EC 203-963-7 (DEDG)
- Substance type: Organic
- Physical state: Colourless liquid
- Analytical purity: 99.95%
- Lot/batch No.: 2E09WA
- Expiration date of the lot/batch: 31 December 2012
- Storage condition of test material: In a refrigerator (2 to 8 degC)
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 53 to 60 days
- Weight at study initiation: 259 to 322 g for males and 190 to 250 g for females
- Fasting period before study:
- Housing: Animals were housed inside a restricted access rodent facility. The facility was designed and operated to minimise the entry of external biological and chemical agents and to minimise the transference of such agents between rooms. Before the study the room was cleaned and disinfected.
The animals were housed five of one sex per cage. The cages were made of a polycarbonate body with a stainless steel mesh lid. Softwood bark-free fibre was used as bedding and was sterilised by autoclaving and changed at appropriate intervals each week. Cages, food
hoppers and water bottles were changed at appropriate intervals.
- Diet (e.g. ad libitum): The animals were allowed free access to a standard rodent diet (Rat and Mouse No. 1
Maintenance Diet), except overnight before routine blood sampling and during exposure. This diet contained no added antibiotic or other chemotherapeutic or prophylactic agent.
- Water (e.g. ad libitum): Potable water taken from the public supply was freely available via polycarbonate bottles fitted with sipper tubes, except during exposure.
- Acclimation period: 11 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 23
- Humidity (%): 40-70
- Air changes (per hr): Each animal room was supplied with filtered fresh air, which was passed to atmosphere and not re-circulated.
- Photoperiod (hrs dark / hrs light):12/12
Administration / exposure
- Route of administration:
- inhalation: aerosol
- Type of inhalation exposure:
- nose only
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Each exposure system consisted of a stainless steel concentric jet atomiser and a snout only ADG exposure chamber. Different doses of DEDG were achieved by varying the concentrations of the test article in the system whilst keeping the duration of exposure constant.
- System of generating particulates/aerosols: Aerosol produced by a stainless steel concentric jet atomiser A narrow bore needle was used
The atomiser was mounted vertically down into the top of the prechamber
- Temperature: The chamber temperatures were similar for each group on each day of the study. The observed temperatures for all groups remained within the normally accepted range for inhalation exposure of rats, as per OECD Guidelines for the Testing of Chemicals Number 412 (22±3°C)
- Air flow rate: Inlet: From in-house compressed air system – breathing quality
Atomiser – 8 L/minute
Diluent – 10L/min
- Extract Airflow:
Drawn by in-house vacuum system
Filtered locally
Flow – 20 L/minute - Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- 6 hours a day, 5 days a week
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
0.25 mg/L
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
0.8 mg/L
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
2.5 mg/L
Basis:
nominal conc.
- No. of animals per sex per dose:
- 10
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: The exposure concentrations (0, 0.25, 0.80 or 2.5 mg/L) were selected following completion of a one week inhalation dose range finding study in rats (Huntingdon Life Sciences Study Number: OOE0008), in which no effects were noted at a target exposure concentration of
2.5 mg/L.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
Pre-exposure observation
During exposure however, observation severely restricted due to tube restraint
As each animal is returned to its home cage
As late as possible in the working day
In addition, a more detailed weekly physical examination was performed on each animal to monitor general health.
During the acclimatisation period, observations of the animals and their cages were recorded at least once per day.
BODY WEIGHT: Yes
- Time schedule for examinations: Twice weekly throughout the treatment and on the day of necropsy
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data but the weight of food supplied to each cage, that remaining and an estimate of any spilled was recorded for the week before treatment started (Week -1), and each week throughout the
treatment period.
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 data
WATER CONSUMPTION: No data
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: Yes
- Time schedule for collection of blood: During Week 4 of treatment (before dosing), blood samples were obtained from all animals
after overnight withdrawal of food. Animals were held under light general anaesthesia induced by isoflurane and blood samples were withdrawn from the sublingual vein.
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: Yes (overnight)
- How many animals: all study animals
CLINICAL CHEMISTRY: Yes
At the same time and using the same animals as for peripheral haematology, further blood samples (nominally 0.7 mL) were collected into tubes containing lithium heparin as anticoagulant. All tubes were mechanically agitated for at least two minutes and the sample subsequently centrifuged at 2000 g for 10 minutes in order to separate the plasma. After separation, the plasma was examined in respect of:
Using a Roche P Modular Analyser:
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Gamma-glutamyl transpeptidase (gGT)
Total bilirubin (Bili)
Urea
Creatinine (Creat)
Glucose (Gluc)
Total cholesterol (Chol)
Triglycerides (Trig)
Sodium (Na)
Potassium (K)
Chloride (Cl)
Calcium (Ca)
Inorganic phosphorus (Phos)
Total protein (Total Prot)
Albumin (Alb)
URINALYSIS: No data
NEUROBEHAVIOURAL EXAMINATION: No data - Other examinations:
- sperm analysis and sperm morphology
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 specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- blood chemistry
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Details on results:
- CLINICAL SIGNS AND MORTALITY
There were no unscheduled deaths on this study.
There were no treatment-related clinical signs observed during the weekly detailed physical examination.
BODY WEIGHT AND WEIGHT GAIN
Bodyweight gain of males exposed to 2.49 mg/L was lower than the concurrent controls over the 4 weeks of treatment (Days 1-29, 0.85X Control). Review of the individual twice weekly bodyweights, however, did not show any consistent effects and as there were no similar effects on the females and the difference was not statistically significant; the lower bodyweight gain in males is considered unrelated to DEDG.
There were no effects of DEDG in males exposed to 0.257 or 0.686 mg/L or any females given DEDG.
FOOD CONSUMPTION
There were no effects of DEDG on food consumption.
HAEMATOLOGY, BONE MARROW
There were no treatment-related effects on the cellularity and composition of the marrow or the myeloid to erythroid ratio.
BLOOD CHEMISTRY
Group mean cholesterol and triglyceride levels were higher than the concurrent controls in all treated male groups. A similar effect was not apparent in females and there was no dose response. There were no corroborating pathological changes to explain these higher levels,
and as there were no similar effects in females and no dose response, these intergroup differences are considered to be of no toxicological significance.
There were no treatment-related effects on the other blood chemistry parameters investigated.
ORGAN WEIGHTS
Group mean adrenal weights (adjusted for bodyweight) of males exposed to 2.49 mg/L were statistically significantly higher than the concurrent control. There was no similar effect in females. Pathological changes in the adrenals correlated with the increased weights, but the adrenal changes were considered likely to be related to the stress of restraint during the inhalation procedure, unlikely to be related to treatment and not adverse.
Group mean liver weight (adjusted for bodyweight) of males exposed to 2.49 mg/L was statistically significantly higher than the concurrent control, but as there was intergroup variability in this parameter, no changes noted for females, and no corroborating pathological changes in the liver this change is considered to be unrelated to treatment.
Other intergroup differences seen were small and largely inconsistent between groups and sexes. Therefore, these were considered to be due to individual variation in results and not to be related to treatment
GROSS PATHOLOGY
The macroscopic examination performed after 4 weeks of treatment revealed no intergroup differences of note.
The nature and incidence of all findings were consistent with the commonly seen background of macroscopic changes in Sprague Dawley rats at these laboratories
HISTOPATHOLOGY: NON-NEOPLASTIC
No findings were seen that were clearly related to treatment with DEDG.
Minimal or slight generalised hypertrophy of the zona fasciculata was seen in three male animals exposed to 2.49 mg/L. This finding correlated with the higher bodyweight-adjusted group mean adrenal weight, compared with male controls, for males exposed to 2.49 mg/L.
In the right testis, seminiferous tubular vacuolation and or cellular debris, and in the right epididymis, degenerative spermatogenic cells and or cellular debris in the ducts, were seen at higher incidences in control males than in males exposed to 2.49 mg/L. Therefore, these
findings were not related to treatment, but were considered possibly related to the stress associated with the inhalation procedure (Dodd, 1999; Lee, 1993) and correlated with the atypical values reported at sperm analysis for control animals.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 2.49 mg/L air (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects up to the highest dose tested..
Target system / organ toxicity
- Critical effects observed:
- no
Any other information on results incl. tables
There was a very low level of DEDG detected at analysis of the samples collected from the control group. In 18/23 occasions the identified peak was below the limit of detection, and in the other 5 samples was very low (approximately 25% that of the low dose levels). It was established that there was a low level of DEDG vapour within the animal room, which could have contaminated the external surfaces of the sampler and possibly absorbed into the trapping solvent used in analysis. Animals of the control group were exposed to clean external fresh air in a sealed system and were considered to have no direct contact with this low level of contamination, and this is considered to have no impact on the study integrity.
Applicant's summary and conclusion
- Conclusions:
- DEDG was administered to Sprague Dawley rats by snout only inhalation exposure for 6 hours a day, 5 days a week for 4 weeks at estimated exposure concentrations of 0.257, 0.686 or 2.49 mg/L.
No adverse treatment related effects were apparent in any of the parameters investigated and DEDG was well tolerated over the 4 week treatment period.
The No Observed Adverse Effect Level (NOAEL) was 2.49 mg/L.
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