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EC number: 203-721-0 | CAS number: 109-94-4
- 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:
- sub-chronic toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- secondary literature
- Justification for type of information:
- Data is from publication
Data source
Reference
- Reference Type:
- publication
- Title:
- A 90-Day Inhalation Toxicity Study of Ethyl Formate in Rats
- Author:
- Mi Ju Lee and Hyeon-Yeong Kim
- Year:
- 2 017
- Bibliographic source:
- Toxicol. Res. Vol. 33, No. 4, pp. 333-342 (2017),
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
- Principles of method if other than guideline:
- Repeated dose inhalation toxicity study of Ethyl Formate in Rats
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Ethyl formate
- EC Number:
- 203-721-0
- EC Name:
- Ethyl formate
- Cas Number:
- 109-94-4
- Molecular formula:
- C3H6O2
- IUPAC Name:
- ethyl formate
- Test material form:
- other: liquid
- Details on test material:
- - Name of test material (as cited in study report): Ethyl formate
- Molecular formula (if other than submission substance): C3H6O2
- Molecular weight (if other than submission substance): 74.0785 g/mol
- Substance type: Organic
- SMILES:CCOC=O
- Physical state: liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Source: Japan SLC., Inc. (Hamamatsu, Japan) via Joongang Experimental Animal Co., Ltd. (Seoul, Korea)
- Age at study initiation: 7 weeks
- Weight at study initiation:
- Fasting period before study:
- Housing: Animals were housed individually in wire-bottomed stainless-steel mesh cages placed in exposure
Chambers.
- Diet (e.g. ad libitum): Commercial
rodent chow (PicoLab Rodent Diet 5053, LabDiet, USA) ad libitum, ad libitum
- Water (e.g. ad libitum): sterilized tap water, ad libitum
- Acclimation period: 1 week
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 50 ± 20%
- Air changes (per hr): 12-15 air changes/hr
- Photoperiod (hrs dark / hrs light): artificial lighting from 08:00 to 20:00
Administration / exposure
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure:
- whole body
- Vehicle:
- air
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Whole-body
exposure chambers (WITC-00-M, HCT Co., Korea)
- Method of holding animals in test chamber: Whole-body
- Source and rate of air:
- Method of conditioning air:
- System of generating particulates/aerosols: LVg-04-A
- Temperature, humidity, pressure in air chamber:23 °C
- Air flow rate:
- Air change rate:
- Method of particle size determination:
- Treatment of exhaust air:
TEST ATMOSPHERE
- Brief description of analytical method used: The ethyl formate levels were detected using gas chromatography (TRACE1310,
Thermo Scientific, China) with the following apparatus: detector, flame ionization detector; column, TraceGold TG- 5MS 5% diphenyl-95% dimethyl polysiloxane capillary column (30 m length, 0.25 mm i.d., 0.25 mm film thickness).
- Samples taken from breathing zone: yes
VEHICLE (if applicable)
- Justification for use and choice of vehicle: fresh air
- Composition of vehicle:
- Type and concentration of dispersant aid (if powder):
- Concentration of test material in vehicle: 0, 66, 330, and 1,320 ppm
- Lot/batch no. of vehicle (if required):
- Purity of vehicle: - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- using gas chromatography
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- 6 hr/day, 5 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/L air (analytical)
- Dose / conc.:
- 0.2 mg/L air (analytical)
- Dose / conc.:
- 1 mg/L air (analytical)
- Dose / conc.:
- 4 mg/L air (analytical)
- No. of animals per sex per dose:
- Total: 80
0 mg/L : 10 male, 10 female
0.2 mg/L : 10 male, 10 female
1 mg/L : 10 male, 10 female
4 mg/L : 10 male, 10 female - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Concentrations of 0, 0.2, 1 and 4 mg/L was selected based on a prior study and the OEL.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Before, during, and after the exposure period
- Cage side observations checked in table [No.?] were included.: Mortality were observed.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Before, during, and after the exposure period
BODY WEIGHT: Yes
- Time schedule for examinations: All the rats were weighed individually on the first exposure day and once a week after that.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
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: Yes / No / No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: On week 12.
- Dose groups that were examined: All doses were examined.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: On day 90 of treatment.
- Anaesthetic used for blood collection: Yes, isoflurane
- Animals fasted: Yes, overnight
- How many animals: All 80 animals were examined.
- Parameters checked in table [No.?] were examined.: Prothrombin time (PT)
and activated partial thromboplastin time (APTT), total red blood cell (RBC) count, hemoglobin (HGB) concentration, hematocrit (HCT), mean cell volume (MCV), mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), platelet (PLT) count, total white blood cell (WBC) count, differential WBC count (neutrophil, lymphocyte, monocyte, eosinophil, and basophil), reticulocyte (Reti) count, PT, and APTT were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: On day 90 of treatment.
- Animals fasted: Yes, overnight
- How many animals: All 80 animals were examined.
- Parameters checked in table [No.?] were examined.: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), blood urea nitrogen
(BUN), creatinine (Crea), total bilirubin (T-Bili), total protein (TP), albumin (Alb), A/G ratio, total cholesterol (TChol), triglyceride (TG), glucose (Glu), potassium (K), calcium (Ca), chloride (Cl), inorganic phosphorus (P), and sodium (Na) were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: on week 13
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.: pH, protein, glucose, ketone body, bilirubin, occult blood, leukocyte, nitrite, urobilinogen, and specific gravity were examined.
NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:
OTHER:
Organ weight:
Absolute and relative adrenals, brain, heart, kidneys, liver, spleen, testes, thymus, epididymides, lung, thyroids, ovaries, and uterus weight were examined. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
External body surfaces and all orifices were examined.
HISTOPATHOLOGY: Yes
Organ/tissues were preserved in 10% neutral buffered formalin:
Organ examined: adrenals, aorta, bone
marrow, brain, cecum, colon, duodenum, epididymides, esophagus, eyes, femur, Harderian glands, heart, ileum, jejunum, kidneys, larynx, liver, lung, lymph nodes (hilar and mesenteric), mammary gland, nasopharyngeal tissue, nerves (optic and sciatic), pancreas, parathyroids, pituitary, prostate, rectum, salivary glands (submandibular, sublingual,
and parotid), seminal vesicles, skeletal muscle, skin, spinal cord (cervical, lumbar, and thoracic), spleen, sternum, stifle joint, stomach, testes, teeth, thymus, thyroids, trachea, urinary bladder, ovaries, and uterus. The eyes/optic nerve and testes were preserved in Davidson’s solution
- Statistics:
- Statistical analysis was performed for body weight, food consumption, hematology and serum biochemistry parameters, organ weights, and organ/body weight. For the control and ethyl formate-exposed groups, the homogeneity of the variance of numerical data was determined using Levene’s test. Groups with homogenous and heterogeneous data were compared using one-way analysis of variance (ANOVA) and non-parametric Kruskal- Wallis test, respectively. If statistical significance was observed (p < 0.05), Dunnett’s test (for ANOVA) or the Steel test (for Kruskal-Wallis) was used for multiple comparisons of the control group with each dose group.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- when treated with 4 mg/L, decrease in locomotor activity of the male and female rats were observed as compared to control, but recovered after the exposure ended.
- Mortality:
- no mortality observed
- Description (incidence):
- No mortality were observed during the study in treated rats as compared to control.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- When treated with 4 mg/L, Body weight gain significantly decreased in male and female rats from week 1 were observed as compared to control rats. Increased body weight gain on week 4 were observed in male rat as compared to control.
When treated with 1 mg/L, increased body weight gain on week 4 in male rats were observed as compared to control.
The increased body weight of the male rats exposed to 330 ppm at week 4 was
not considered to be ethyl formate-related change because they were isolated changes. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- When treated with 4 mg/L, significantly decreased in male and female rat were observed from week 1 and week 3, respectively as compared to control.
- 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
- Description (incidence and severity):
- When treated with 4 mg/L, increased HGB and HCT level in male and decreased in Reti level n female rat were observed as compared to control.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- When treated with 4 mg/L, Ca and TG levels decreased in male and female rats respectively.
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- When treated with 4 mg/L, incerase in Ketone body in male and femlae rat and Urobilinogen level in female rat were observed as compared to control.
When treated with 1 mg/L, incerase in Ketone body in femlae rat were observed as compared to control.
Reduced body weight and food consumption are occasionally accompanied by increase in urinary ketone levels, because energy metabolism under those conditions shifts from gluconeogenesis to incomplete oxidation of fatty acids. - Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- When treated with 4 mg/L, absolute and relative adrenal weight increased in male and female rats and relative brain, kidney, and lung in male and female rat as compered to control.
Absolute or relative thymus weight or both decreased in male and female rats and absolute heart, kidney, liver, lung, and spleen weights decreased as compered to control. - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- All the macroscopic findings of the eye, liver, and ovaries were considered to be incidental and of no toxicological significance.
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- When treated with 4 mg/L, Degeneration, Squamous metaplasia and Lesions were mainly noted in the dorsal meatus and occasionally in the septum and turbinate in male and female rats as compared to control.
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
Effect levels
- Dose descriptor:
- NOAEC
- Effect level:
- 1 mg/L air (analytical)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- gross pathology
- haematology
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- urinalysis
- Remarks on result:
- other: No effect observed
Target system / organ toxicity
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
Applicant's summary and conclusion
- Conclusions:
- NOAEC was considered to 1 mg/L when Sprague-Dawley male and female rats were inhaled with test substance for 90 days.
- Executive summary:
In a Repeated dose inhalation toxicity study, Sprague-Dawley male and female rats were inhaled with test substance in the concentration of 0, 0.2, 1 and 4 mg/L for 6 hr/day, 5 days by Whole body exposure for 90 days. Decrease in locomotor activity of the male and female rats were observed as compared to control, but recovered after the exposure ended at 4 mg/L. No mortality was observed during the study in treated rats as compared to control. Body weight gain significantly decreased in male and female rats from week 1 were observed as compared to control rats. Increased body weight gain on week 4 were observed in male rat as compared to control at 4 mg/L and increased body weight gain on week 4 in male rats were observed as compared to control at 1 mg/L. The increased body weight of the male rats exposed to 330 ppm at week 4 was not considered to be ethyl formate-related change because they were isolated changes. Significantly decreased in male and female rat were observed from week 1 and week 3, respectively as compared to control at 4 mg/L. Similarly, increased HGB and HCT level in male and decreased in Reti level n female rat were observed as compared to control and Ca and TG levels decreased in male and female rats respectively at 4 mg/L. Increase in Ketone body in male and female rat and Urobilinogen level in female rat were observed as compared to control. Increase in Ketone body in female rat were observed as compared to control at 1 mg/L. Reduced body weight and food consumption are occasionally accompanied by increase in urinary ketone levels, because energy metabolism under those conditions shifts from gluconeogenesis to incomplete oxidation of fatty acids. In addition, absolute and relative adrenal weight increased in male and female rats and relative brain, kidney, and lung in male and female rat as compared to control and Absolute or relative thymus weight or both decreased in male and female rats and absolute heart, kidney, liver, lung, and spleen weights decreased as compared to control at 4 mg/L. Degeneration, Squamous metaplasia and Lesions were mainly noted in the dorsal meatus and occasionally in the septum and turbinate in male and female rats as compared to control at 4 mg/L. Therefore, NOAEC was considered to 1 mg/L when Sprague-Dawley male and female rats were inhaled with test substance for 90 days.
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