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EC number: 207-330-6 | CAS number: 462-95-3
- 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:
- short-term repeated dose toxicity: oral
- Remarks:
- It is a 14-day preliminary toxicity study.
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 28 March 2018 - 18 April 2018
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The study generally followed Good Laboratory Practice principles.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
Materials and methods
- Principles of method if other than guideline:
- The study was not designed to meet any particular regulatory requirements. No claim for compliance with Good Laboratory Practice was made, although the work performed generally followed Good Laboratory Practice principles.
- GLP compliance:
- not specified
Test material
- Reference substance name:
- Diethoxymethane
- EC Number:
- 207-330-6
- EC Name:
- Diethoxymethane
- Cas Number:
- 462-95-3
- Molecular formula:
- C5H12O2
- IUPAC Name:
- diethoxymethane
- Test material form:
- liquid
- Details on test material:
- Identification: Diethoxymethane
Synonym: Ethylal
CAS Number: 462-95-3
Physical State/Appearance: Clear colourless liquid
Storage Conditions: Approximately 4 °C, in the dark, under nitrogen
No correction for purity was required.
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Batch No.of test material: 1709141400R
- Expiration date of the batch: 14 September 2019
- Purity: 99.987%
- Appearance: Colorless liquid.
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Under nitrogen, refrigerated (2 to 8°C) and protected from light (highly volatile). Allowed to return to room temperature (15 to 25°C) before opening the bottle.
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- Crl:CD(SD) rat.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation:
Males: 70 to 77 days, Females: 84 to 91 days
- Weight at study initiation:
Males: 336 to 395 g, Females: 257 to 292 g
- Housing:
Polycarbonate body with a stainless steel mesh lid, changed at appropriate intervals.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period:
Seven days before commencement of treatment.
ENVIRONMENTAL CONDITIONS
- Temperature (°C):
20-24
- Humidity (%):
40-70
- Air changes: Filtered fresh air which was passed to atmosphere and not recirculated.
- Photoperiod (hrs dark / hrs light):
Artificial lighting, 12 hours light : 12 hours dark.
IN-LIFE DATES: From: 28 March 2018 To:18 April 2018
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- Oral, by gavage, using a suitably graduated syringe and a rubber catheter inserted via the mouth.
- Vehicle:
- corn oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The required amount of test item was mixed with a small quantity of the vehicle. Approximately 20% of the final volume of vehicle was gradually added. The formulation was quantitatively transferred and diluted to final volume and magnetically stirred in a sealed container of appropriate size ensuring there is no head space. Homogeneity and stability of the preparation were assessed in another study (KG04BG)
VEHICLE
- Concentration in vehicle:
0, 60, 120, 200 mg/mL - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 14 days
- Frequency of treatment:
- Once daily at approximately the same time each day
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 600 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 3
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Rationale for Dose Level Selection:
The doses used in this study (0, 300, 600 and 1000 mg/kg/day) were selected in conjunction with the Sponsor.
The oral LD50 in rats appears to be 3536 mg/kg bw.
A previous acute oral toxicity study conducted on the test material found that a single dose to rats of 5000 mg/kg caused mortality within 24 hours administration (4 of 5 animals). Signs of toxicity included ataxia, weakness (slight to severe) and prostration. Ataxia, weakness (slight to severe) was observed in the other animals administered with test article at a dose of 1250 or 2500 mg/kg, but there were no deaths at these levels.
Based on these results, to aid in determining dose levels for the subsequent OECD 421 study, dose levels of 1000 mg/kg/day (limit dose) 600 and 300 mg/kg/day were studied to define a high dose to induce toxicity but not death or of a severity to compromise interpretation of the results and a low dose, free of adverse effects with repeated administration according to the study design. The intermediate dose was approximately the geometric mean between the high and low dose levels.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: The weight of each animal was recorded three days before treatment commenced, on the day that treatment commenced (Day 1), on Day 4, 8 and 11 of the study and before necropsy on Day 15.
- Sacrifice and pathology:
- All 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.
The retained tissues were checked before disposal of the carcass.
The organs weighed and tissue samples fixed are detailed as follows:
Abnormalities: Organs weighed and samples fixed.
Kidneys: Bilateral organs weighed individually and samples fixed.
Liver: Organs weighed and samples fixed.
Spleen: Organs weighed and samples fixed.
The list of tissues preserved was intended to satisfy any possible future requirement for further examination. - Statistics:
- No statistical analysis of the data was performed on this study.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Table 1
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Table 2
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Table 3
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The analysis of absolute organ weights for animals killed after 14 days of treatment indicated, when compared to the Controls, an increase in the weight of the liver in males and females treated with 600 mg/kg/day of Ethylal, and an increase of kidney weight in males treated with 600 or 1000 mg/kg/day of Ethylal, but no dose response was apparent.
Table 4 - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Table 5
Any other information on results incl. tables
|
Control |
Ethylal |
||
Dose group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
300 |
600 |
1000 |
Table 1: Signs associated with dosing - group distribution of observations
|
Number of animals affected |
||||||||||
Category |
Observation |
Day |
Group/Sex: Initial no: |
1M 3 |
2M 3 |
3M 3 |
4M 3 |
1F 3 |
2F 3 |
3F 3 |
4F 3 |
Abnormal gait |
Unsteady |
1 2 |
|
0 0 |
0 0 |
0 0 |
3 1 |
0 0 |
0 0 |
0 0 |
2 0 |
Behavior |
Decreased activity |
1 2 |
0 0 |
0 0 |
1 0 |
3 1 |
0 0 |
0 0 |
1 0 |
3 0 |
|
Coat |
Piloerection |
2 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
|
Eyelids |
Partially closed, Bilateral |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
Table 2: Body weight - group mean values (g)
Group /sex |
|
Day P4 |
Day 1 |
4 |
8 |
11 |
Change 1-15 |
1M |
Mean |
350 |
367 |
380 |
382 |
398 |
49 |
|
SD |
25.3 |
26.8 |
25.4 |
41.8 |
33.5 |
9.3 |
|
N |
3 |
3 |
3 |
3 |
3 |
3 |
2M |
Mean |
343 |
361 |
374 |
386 |
395 |
54 |
|
SD |
8.3 |
3.4 |
9.2 |
2.5 |
6.6 |
2.6 |
|
N |
3 |
3 |
3 |
3 |
3 |
3 |
3M |
Mean |
343 |
361 |
376 |
392 |
406 |
61 |
|
SD |
11.6 |
13.1 |
14.8 |
14.2 |
19.0 |
10.9 |
|
N |
3 |
3 |
3 |
3 |
3 |
3 |
4M |
Mean |
350 |
367 |
375 |
392 |
400 |
49 |
|
SD |
21.8 |
24.4 |
19.1 |
22.4 |
25.9 |
12.7 |
|
N |
3 |
3 |
3 |
3 |
3 |
3 |
Group /sex |
|
Day P4 |
Day 1 |
4 |
8 |
11 |
15 |
Change 1-15 |
1F |
Mean |
264 |
275 |
268 |
279 |
280 |
284 |
9 |
|
SD |
4.8 |
12.1 |
4.6 |
3.5 |
3.6 |
8.1 |
4.8 |
|
N |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
2F |
Mean |
259 |
274 |
276 |
283 |
285 |
288 |
15 |
|
SD |
12.0 |
12.0 |
8.6 |
7.1 |
9.1 |
8.8 |
17.8 |
|
N |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
3F |
Mean |
269 |
271 |
277 |
284 |
289 |
297 |
26 |
|
SD |
6.1 |
13.9 |
12.2 |
18.0 |
18.3 |
22.6 |
10.1 |
|
N |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
4F |
Mean |
271 |
278 |
282 |
289 |
292 |
300 |
22 |
|
SD |
20.7 |
11.9 |
19.4 |
19.5 |
28.1 |
26.9 |
15.0 |
|
N |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
Table 3: Food consumption - group mean values (g/animal/day)
Group /sex |
|
Day P4-P7 |
Day 1-4 |
4-8 |
8-11 |
11-15 |
Mean 1-15 |
1M |
Mean |
28 |
23 |
22 |
22 |
23 |
23 |
|
SD |
- |
- |
- |
- |
- |
- |
|
N |
1 |
1 |
1 |
1 |
1 |
1 |
2M |
Mean |
28 |
23 |
23 |
24 |
23 |
23 |
|
SD |
- |
- |
- |
- |
- |
- |
|
N |
1 |
1 |
1 |
1 |
1 |
1 |
3M |
Mean |
31 |
26 |
25 |
26 |
25 |
26 |
|
SD |
- |
- |
- |
- |
- |
- |
|
N |
1 |
1 |
1 |
1 |
1 |
1 |
4M |
Mean |
30 |
24 |
24 |
25 |
24 |
24 |
|
SD |
- |
- |
- |
- |
- |
- |
|
N |
1 |
1 |
1 |
1 |
1 |
1 |
Group /sex |
|
Day P4-P7 |
Day 1-4 |
4-8 |
8-11 |
11-15 |
Mean 1-15 |
1F |
Mean |
20 |
13 |
18 |
17 |
17 |
16 |
|
SD |
- |
- |
- |
- |
- |
- |
|
N |
1 |
1 |
1 |
1 |
1 |
1 |
2F |
Mean |
22 |
17 |
17 |
17 |
17 |
17 |
|
SD |
- |
- |
- |
- |
- |
- |
|
N |
1 |
1 |
1 |
1 |
1 |
1 |
3F |
Mean |
20 |
17 |
17 |
16 |
17 |
17 |
|
SD |
- |
- |
- |
- |
- |
- |
|
N |
1 |
1 |
1 |
1 |
1 |
1 |
4F |
Mean |
24 |
17 |
18 |
18 |
18 |
18 |
|
SD |
- |
- |
- |
- |
- |
- |
|
N |
1 |
1 |
1 |
1 |
1 |
1 |
Table 4: Organ weights - group mean absolute values (g) for animals killed after 14 days of treatment
Group /sex |
|
Terminal Bodyweight |
Kidneys |
Liver |
Spleen |
1M |
Mean |
414 |
2.914 |
17.390 |
0.747 |
|
SD |
32 |
0.330 |
1.717 |
0.082 |
|
N |
3 |
3 |
3 |
3 |
2M |
Mean |
411 |
3.085 |
18.481 |
0.702 |
|
SD |
2 |
0.255 |
1.080 |
0.037 |
|
N |
3 |
3 |
3 |
3 |
3M |
Mean |
421 |
3.325 |
19.236 |
0.684 |
|
SD |
24 |
0.202 |
2.273 |
0.047 |
|
N |
3 |
3 |
3 |
3 |
4M |
Mean |
419 |
3.242 |
18.257 |
0.805 |
|
SD |
25 |
0.126 |
1.352 |
0.078 |
|
N |
3 |
3 |
3 |
3 |
Group /sex |
|
Terminal Bodyweight |
Kidneys |
Liver |
Spleen |
1F |
Mean |
285 |
2.019 |
11.556 |
0.591 |
|
SD |
6 |
0.081 |
1.168 |
0.077 |
|
N |
3 |
3 |
3 |
3 |
2F |
Mean |
291 |
2.268 |
12.093 |
0.658 |
|
SD |
7 |
0.180 |
0.435 |
0.118 |
|
N |
3 |
3 |
3 |
3 |
3F |
Mean |
298 |
2.105 |
13.703 |
0.638 |
|
SD |
22 |
0.244 |
1.666 |
0.030 |
|
N |
3 |
3 |
3 |
3 |
4F |
Mean |
300 |
1.947 |
12.125 |
0.656 |
|
SD |
26 |
0.246 |
1.112 |
0.141 |
|
N |
3 |
3 |
3 |
3 |
Table 5: Macropathology - group distribution of findings for animals killed after 14 days of treatment
|
Number of animals affected |
||||||||
Tissue/Organ and Findings |
Group/Sex No. of animals |
1M 3 |
2M 3 |
3M 3 |
4M 3 |
1F 3 |
2F 3 |
3F 3 |
4F 3 |
Number of animals within normal limits |
|
3 |
3 |
3 |
3 |
3 |
3 |
2 |
3 |
Skin and Subcutis Hair Loss |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
Applicant's summary and conclusion
- Conclusions:
- Based on the results of this study, treatment with the test item, Ethylal, was well tolerated at oral doses up to 1000 mg/kg/day for 14 days. Therefore, it was concluded that 1000 mg/kg/day would be a suitable high dose level for the subsequent Reproductive/Development Toxicity Screening Study in the Sprague Dawley rat by Oral Gavage Administration (OECD 421)
- Executive summary:
The purpose of this study was to assess the systemic toxic potential of Ethylal in a 14-day oral gavage study in Sprague Dawley rats, to select suitable doses for a subsequent reproduction/developmental toxicity screening test (OECD TG 421).
Three groups, each comprising three male and three female Sprague Dawley (Crl:CD(SD)) rats, received Ethylal at doses of 300, 600 or 1000 mg/kg/day. A similarly constituted control group received the vehicle, corn oil, at the same volume dose as treated groups.
During the study, clinical condition, body weight, food consumption, visual water consumption, organ weight and macropathology investigations were undertaken.
Results
All animals survived to the scheduled sacrifice. Post dose signs of decreased activity and unsteady gait were seen on Day 1 of treatment at 1000 mg/kg/day, and in one male on Day 2 at this dose level.
There were no treatment related clinical observations, no adverse effects on bodyweight gain or food intake, and no changes in water consumption. The organ weights of the liver and kidney were slightly high in animals treated at 600 mg/kg/day and of the kidney of males at 1000 mg/kg/day. The spleen weight was unaffected by treatment.
There were no treatment related findings seen at macroscopic examination.
Conclusion
Based on the results of this study, treatment with the test item, Ethylal, was well tolerated at oral doses up to 1000 mg/kg/day for 14 days. Therefore, it was concluded that 1000 mg/kg/day would be a suitable high dose level for the subsequent Reproductive/Development Toxicity Screening Study in the Sprague Dawley rat by Oral Gavage Administration (OECD 421)
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