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EC number: 201-061-8 | CAS number: 77-83-8
- 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:
- No data
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Meets generally accepted scientific standards, well documented and acceptable for assessment
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 978
- Report date:
- 1977
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Rats were fed 3 different concentrations of test material (plus control) for 15 wk. Body weights and food consumption were measured periodically. After 15 wk the rats were killed and examined. Rats were also killed and examined at 2 and 6 wks.
- GLP compliance:
- no
- Remarks:
- Study predates GLP
Test material
- Reference substance name:
- Ethyl 2,3-epoxy-3-phenylbutyrate
- EC Number:
- 201-061-8
- EC Name:
- Ethyl 2,3-epoxy-3-phenylbutyrate
- Cas Number:
- 77-83-8
- Molecular formula:
- C₁₂H₁₄O₃
- IUPAC Name:
- ethyl 3-methyl-3-phenyloxirane-2-carboxylate
- Details on test material:
- - Name of test material: Ethyl methylphenylglycidate; EMPG
- Substance type: Flavouring used in food stuffs
- Physical state: No data
- Analytical purity: 99.0 %
- Impurities (identity and concentrations): No data
- Composition of test material, percentage of components:
- Isomers composition: 2 isomers, cis- and trans-
- Purity test date: No data
- Lot/batch No.: No data
- Expiration date of the lot/batch: No data
- Stability under test conditions: No data
- Storage condition of test material: No data
- Source: Givaudan & Co. Ltd, Whyteleafe, Surrey
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, United Kingdom
- Age at study initiation: No data
- Weight at study initiation: Average per test group, of 79 g to 84 g
- Fasting period before study: No data
- Housing: 5 per cage.
- Diet: Ground Spiller's animal diet
- Water: ad libitum
- Acclimation period: No data
ENVIRONMENTAL CONDITIONS
- Temperature: No data
- Humidity: No data
- Air changes: No data
- Photoperiod: No data
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- test group 1: 15 wk
test group 2: 2 wk
test group 3: 6 wk - Frequency of treatment:
- Continuous - test material included in diet.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0.5 other: Percent
- Remarks:
- 500 mg/kg bw/day
- Dose / conc.:
- 0.1 other: Percent
- Remarks:
- 100 mg/kg bw/day
- Dose / conc.:
- 0.02 other: Percent
- Remarks:
- 20 mg/kg bw/day
- No. of animals per sex per dose:
- Test group 1: 15 rats per sex per dose (3 doses + control)
Test group 2: 5 rats per sex per dose (2 doses + control; 0.02 % dose not used)
Test group 3: 5 rats per sex per dose (2 doses + control; 0.02 % dose not used) - Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: Based on previously published papers on the toxicity of the test material.
- Positive control:
- None
Examinations
- Observations and examinations performed and frequency:
- CAGE-SIDE OBSERVATIONS: Yes, details unclear
BODY WEIGHT
- Time schedule for examinations: day 1, day 2, day 6, day 8, weekly thereafter
- Data are given for day 0, day 22, day 48, day 98
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight
- Time schedule for examinations: day 1, day 2, day 6, day 8, weekly thereafter
- Data are given for day 0, day 22, day 48, day 98
WATER CONSUMPTION
- Time schedule for examinations: 24 hrs preceding weighing; day 1, day 2, day 6, day 8, weekly thereafter.
- Data are given for day 0, day 22, day 48, day 98
URINALYSIS
- Time schedule for collection of urine: Collected during the final week of treatment.
- Animals fasted: No
- Examined for appearance and for the presence of blood, bile salts, protein, ketones, glucose and microscopic constituents.
RENAL FUNCTION
- Time schedule for collection of urine: wk 2, wk 6, wk 13
- Volume and specific gravity of urine produced measured under 3 sets of conditions:
-- 6 hr period of water deprivation
-- 2 hr period following water load of 25 mL/kg
-- 4 hr period following 16 hr water deprivation
- The number of cells was counted in the 2 hr urine sample.
NEUROBEHAVIOURAL EXAMINATION
- Time schedule for examinations: At unspecified intervals.
- Dose groups that were examined: control group, highest dose group (0.5 %).
- Battery of functions tested: motor activity
- A Rotarod was used to assess the co-ordinated motor activity of the animals during the treatment period. The Rotarod consisted of a wooden cylinder, 8 cm in diameter and 12 cm long, bounded at each end by flanges 135 cm in diameter. The cylinder was rotated at 11 revs/min and the animals' ability to remain on the rotating cylinder was assessed. The criteria of adequate performance were that an animal should remain on the rotating rod for a 3 min period of uninterrupted activity and that this should be achieved within ten attempts. - Sacrifice and pathology:
- GROSS PATHOLOGY
- A post-mortem examination was carried out and any macroscopic abnormalities noted.
HISTOPATHOLOGY
- At autopsy.
- Brain, heart, liver, spleen, kidneys, stomach, small intestine, caecum, adrenals, gonads, pituitary and thyroids weighed.
- Samples of Brain, heart, liver, spleen, kidneys, stomach, small intestine, caecum, adrenals, gonads, pituitary thyroids, salivary gland, trachea, aorta, lung, lymph nodes, urinary bladder, colon, rectum, pancreas, uterus, skeletal muscle and sciatic and brachial nerves were preserved in 10% buffered formalin.
- Paraffin-wax sections were prepared from all tissues from the control rats and from those fed diet containing 0.5 % test material and from the heart, liver, kidneys and spleen of the animals fed the intermediate dietary levels.
- Tissue sections were stained with haematoxylin and eosin with the exception of the peripheral nerves, which were embedded separately and stained with Luxol fast blue and Cresyl fast violet to demonstrate myelin.
HAEMATOLOGY
- Time schedule for collection of blood: At autopsy
- Animals fasted: Yes, overnight prior to being killed
- Examined for erythrocyte count, leucocyte count.
- Fixed and vitally-stained preparations were prepared from all animals for enumeration of reticulocytes and differential leucocytes, but in the absence of changes in the other haematological parameters, examination of these slides was restricted to those from the control animals and from rats fed diet containing 0.5 % test material at wk 6 and 15.
- Serum separated from the blood collected at autopsy from the rats killed at wk 15 was analysed for urea, glucose, albumin and total protein as well as for the activities of glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase and lactic dehydrogenase.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- with respect to renal function; see below.
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Other effects:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
- There were no abnormalities in either condition or general behaviour in animals.
- There were no mortalities during the study.
BODY WEIGHT AND WEIGHT GAIN
- In male 0.02 % level rats, body weights were higher than of the controls to a statistically significant degree (days 29 to 62).
FOOD CONSUMPTION AND COMPOUND INTAKE
- Mean daily food in similar in all groups for a given sex.
- The growth patterns of both male and female rats fed diets containing the test material were similar to those of the control animals. The higher mean body weight values in the male rats fed diet containing 0.02 % test material were not found at any other dietary level or in the female rats at any treatment level.
WATER CONSUMPTION
- Data not discussed by Mason et al.
URINALYSIS
- Data not discussed by Mason et al.
RENAL FUNCTION
- Renal function was unimpaired in the animals fed diets containing 0.5 % EMPG for 13 wk.
- At wk 2 the male rats fed 0.5 % test material induced a smaller volume of urine of a higher specific gravity in the 2 hr period following a water load, although these differences from control values were not statistically significant. The volume of urine collected from this group of animals during the first 6 hr of water deprivation was approximately 50 % of the control value. These data indicate a mild impairment of the ability of the animals to dilute and concentrate urine. There was, however, no increase in the rate of urinary cell excretion.
NEUROBEHAVIOUR
- The mean number of trials required to attain the criterion of 3 min of continuous activity and the number of failures did not differ significantly between the control rats and those fed diet containing 0.5 % test material.
- Data not given in the paper.
HAEMATOLOGY
- There was a lower white blood cell count at wk 6 in the male rats fed 0.5 % test material but there were no other significant findings.
- At wk 15 the level of serum glutamic oxaloacetic transaminase activity was significantly lower in the female rats fed diets containing 0.5% EMPG than in the controls although no similar changes in the male rats.
- No significant increases in the total number of white cells or in the activities of the serum enzymes were observed.
- The isolated lower values of white cells and of glutamic-oxaloacetic transaminase were considered by Mason et al. to be of no toxicological significance.
ORGAN WEIGHTS
- At wk 2, the weights of the empty caecum in the male animals fed 0.1 % or 0.5 % were higher than those of the controls, the differences being statistically significant. However, when expressed relative to body weight the caecum weights did not differ from the control values. Mason et al. conclude that the slight increase in body weights in these animals was the prime factor responsible for these changes.
- After treatment for 6 wk the only statistically significant differences from control values were higher small-intestine weights in female rats fed 0.5 % test material and lower relative stomach weights in male rats fed 0.1 % test material.
- The increased absolute and relative weights of empty caecum, small intestine and stomach found in the female rats fed 0.5 % test material for 15 wk were not found in the male rats fed the same dietary level nor did there appear to be a dose-related effect in the female rats.
- In view of the absence of any histopathology in gastro-intestinal tract tissues, it is difficult to reconcile the increases in weight of the gastro-intestinal tract with any adverse effect of the test material, although the presence of these changes at both 6 and 15 wk in animals fed the same dietary level of the test material suggests that they were related to treatment.
- At autopsy in wk 2 of the male rats fed 0.5 % test material all the kidneys absolute and relative weights were higher than in the corresponding male control rats.
- In the female rats fed 0.1 % test material the pituitary weights were higher than in the controls. Although these increases were statistically significant they were not evident when the weights were expressed relative to body weight.
- The increases in the relative liver weights found in the males and females fed 0.5 % test material at wk 15 were regarded by Mason et al. as being related to treatment, although there was no evidence of histological change.
- The increased liver weight in the male rats fed 0.02 % test material for 15 wk was not evident when expressed relative to body weight and therefore was considered to be unrelated to treatment.
- The increased relative spleen weight in the female rats fed 0.5% EMPG for 15 wk was also probably unrelated
to treatment, since it was not found in any other group of animals.
HISTOPATHOLOGY:
- In the kidneys at wk 2 autopsy of the male rats fed 0.5 % test material, several areas of dense lymphocytic infiltration surrounding both tubules and glomeruli in the cortical area were found. In general the cells in these areas appeared pale and swollen. In the lumen of a few tubules, desquamated cells could be identified, some of which appeared necrotic. Although generally the glomeruli appeared normal, slight thickening of Bowman’s capsule was observed in the areas. These changes to the kidneys, consistent with an early stage of nephrosis, were found in 2/5 animals in the corresponding control group and in 1/5 and 2/5 females in the control group and the group given 0.5% level in their diet respectively for 2 wk. At wk 6, 4/5 male control rats, 2/5 males fed 0.5 % test material and one female rat fed 0.5 % test material had similar lesions. Incidences of early nephrosis in the animals killed at wk 15 are shown in the supporting information.
- In view of the frequent appearance of these lesions, particularly among male rats, and their occurrence in both control and treated animals in the present experiment, it is unlikely that they represent an effect of treatment.
- The relative kidney enlargement found at wk 15 in both male and female rats fed 0.5% test material was not accompanied by either impaired renal function or any histological changes, but the low probability of observing kidney-weight increases of this magnitude by chance suggests that the finding was related to the ingestion of the test material.
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 500 mg/kg diet
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 100 mg/kg diet
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Overall effects
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Histopathology results:
Incidence of pathological reasons in | |||||
Males at dietary level (%) of | Females at dietary level (%) of | ||||
0 | 0.5 | 0 | 0.5 | ||
Tissue and histological finding | No. of animals examined: | 12 | 15 | 14 | 15 |
Lungs | |||||
- Severe pneumonitis | 2 | 2 | 3 | 1 | |
- Slight to moderate infection | 7 | 12 | 5 | 7 | |
Kidney | |||||
- Early nephrosis | 2 | 2 | 1 | 0 | |
Liver | |||||
- Small area of necrosis | 1 | 0 | 0 | 1 | |
- Perivascular cuffing | 0 | 1 | 0 | 0 | |
- Embolus | 0 | 0 | 1 | 0 | |
- Area of old haemorrhage | 0 | 0 | 0 | 1 | |
Sciatic nerve | |||||
- Vacuolation | 4 | 4 | 10 | 13 | |
- Mast cells present | 6 | 8 | 12 | 14 | |
- Birefringent deposits in microglial cells | 0 | 0 | 5 | 4 |
The figures indicate the number of animals affected. The incidences in the treated and control animals did not differ significantly (P>0.05 by Pearson's χ² test.
Applicant's summary and conclusion
- Conclusions:
- Mason et al. found that the NOAEL of the test material was at the 0.5 % level in diet (500 mg/kg bw/day).
Mason et al. found that the NOEL of the test material was at the 0.01 % level in diet (100 mg/kg bw/day).
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