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EC number: 228-985-4 | CAS number: 6386-38-5
- 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:
- 1969
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: very old study, non GLP and non guideline study, very young rats were used, only limited hematology parameters analyzed, limited clinical chemistry, no urinalysis, no details on compound intake, no individual results reported.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 969
- Report date:
- 1969
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The test article was administered orally over 90 days at dosing levels of 0.04, 0.2 and 1 % in the diet to young albino Wistar rats. The following parameters were analyzed: body weight, food consumption and food efficiency, hematology parameters (hemoglobin content, packed cell volume, red blood cell counts and total and differential white blood cell counts), clinical chemistry (serum glutamic-pyruvic transaminase (SGPT), serum glutamic-oxaloacetic transaminase (SGOT), serum alkaline phospahatase (SAP), serum ornithine carbamyl transferase (SOCT) and total serum proteins (TSP)). In addition, gross pathology was performed and the following organs were weighed: heart, liver, kidney, spleen, brain, testicle/ovary, thymus, pituitary, thyroid and adrenal. Detailed microscopic examination was performed on all surviving male and female rats of the highest dose group and of all control rats.
- GLP compliance:
- no
Test material
- Reference substance name:
- Methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate
- EC Number:
- 228-985-4
- EC Name:
- Methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate
- Cas Number:
- 6386-38-5
- Molecular formula:
- C18H28O3
- IUPAC Name:
- methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoate
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: CIVO-colony
- Age at study initiation: weanling rats
- Weight at study initiation: males: 57.5 g, females: 52 g (average values)
- Housing: in screen bottom cages (five to a cage)
- Diet: stock diet consisting of: 28% yellow maize, 26% whole wheat, 10% rolled oats, 10% soybean oil meal, 8% fish meal, 4% meat scraps, 2.7% dried whey, 3% soybean oil, 3% grass meal, 1.5% minerals, 0.5 % sodium chloride, 3.3% vitamin preparations, ad libitum
- Water: tap water, ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test compound was thoroughly mixed into the diet by means of a mechanical blender (type Lodige, Paderborn).
DIET PREPARATION
- Rate of preparation of diet (frequency): every 2 weeks - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- continuously in food
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 0.04, 0.2 and 1.0 %
Basis:
nominal in diet
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: The dose levels were based on a range finder where feeding of dietary levels of 1.0 and 5.0 % resulted in deaths, decreased
growth rate, diminished food intake, increased water intake, increased relative weight of liver and damage of liver and kidney. At 0.2 % the only effect was an increase in liver weight (report nr. R 276U).
- Rationale for animal assignment (if not random): by weight
Examinations
- Observations and examinations performed and frequency:
- BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION:
- Time schedule for examinations: during the first four weeks and in week 11 and 12.
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption: Yes
HAEMATOLOGY: Yes
- Time schedule for collection of blood: in the 12th week
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- Parameters checked: haemoglobin content, packed cell volume, red blood cell counts and total and differential white blood cell counts
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the study
- Animals fasted: No data
- Parameters checked: serum glutamic-pyruvic transaminase (SGPT), serum glutamic-oxaloacetic transaminase (SGOT), serum alkaline phosphatase (SAP), serum ornithine carbamyl transferase (SOCT) and total serum proteins (TSP) - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
In the 14th week all rats were killed by decapitation and examined macroscopically for pathological changes. The following organs were weighed: heart, liver, kidney, spleen, brain, testicle/ovary, thymus, pituitary, thyroid and adrenal. Samples of these organs and of a wide range of other organs were fixed in a 4 % neutralized formaldehyde solution.
HISTOPATHOLOGY: Yes
Detailed microscopic examination was performed on all surviving male and female rats of the highest dose group and of all control rats. Haematoxylin-eosin stained paraffin sections of the organs weighed and also of the following organs were examined: lung, salivary glands (sublingual, submaxillary and parotid gland) esophagus, Harderian gland, stomach, duodenum, ileum, caecum, colon, trachea, skeletal muscle, aorta, exorbital lacrimal gland, auxillary and mesenteric lymph nodes, pancreas, skin, urinary bladder, bone marrow (sternum), prostate, epididymis, coagulating gland, seminal vesicle, preputial gland, uterus, spinal cord and femoral nerve. Microscopic examination of rats at lower dosage levels (0.04 and 0.2 %) was restricted to liver, kidney, thyroid, thymus, stomach, testicle, submaxillary gland, ovary, uterus, adrenal and heart. A number of frozen kidney sections was stained with Sudan III. Selected paraffin liver sections were stained with PAS, Luxol fast blue, and according to Perl's method for iron. The latter procedure was also applied to a few kidney sections. In addition, a number of selected paraffin sections of the adrenals was stained according to Van Gieson's method for connective tissue.
Results and discussion
Results of examinations
- Details on results:
- CLINICAL SIGNS AND MORTALITY
Eight male and six female rats fed on 1 % test substance died during the experimental period. Most deaths occurred during the second and third
week of the experiment. Otherwise no abnormalities in condition or behavior were observed.
BODY WEIGHT AND WEIGHT GAIN
Considerable growth depression occurred at 1 % in either sex. At the 0.04 and 0.2 % the body weight figures were comparable to those of the
controls.
FOOD CONSUMPTION AND FOOD EFFICIENCY
The food intake of the 1 % group was distinctly diminished in either sex. At lower levels food consumption as well as food efficiency figures were not distinctly different from those of the controls.
HAEMATOLOGY
Haemoglobin content and number of white blood cells were significantly decreased at 1 % in either sex. At lower dosage levels the haematoglogical data were comparable to those of the controls.
CLINICAL CHEMISTRY
The SGOT-activities at 0.2 and 1 % were lower than those of the controls in either sex. In females the differences were statistically significant. Alkaline phosphatase activities were increased in male and female rats at the highest level. The slightly higher SAP value in males at 0.04 % did not suggest any relationship with the level of the test substance. Total serum protein, SGPT and SOCT values were comparable in all groups in both sexes.
ORGAN WEIGHTS
At the feeding level of 1.0 % several organ weights differed considerably from those of the controls. This may partly be ascribed to the very low body weights in this group. At the 0.2 % level liver weights and thyroid weights were increased in both sexes. Thyroid weights were also slightly increased in males at the 0.04 % level.
GROSS PATHOLOGY
The surviving animals of the highest dose-group were small and emaciated. All of them had enlarged, dark-brown livers and large thyroids. In addition, one of the two male survivors in this group showed severe pulmonary emphysema and atrophy of both testicles, prostate and seminal vesicle.
At lower dosage levels the gross post mortem examination did not reveal treatment-related pathological changes. Other lesions noted at necropsy, in the test groups and in the control group, such as early signs of murine pneumonia and proteinaceous plugs in the urinary bladder, are regularly seen in the strain of rats used. They may, therefore, not be ascribed to the ingestion of the test article.
HISTOPATHOLOGY
At microscopic examination the most outstanding treatment-related pathological changes were found in liver and thyroid.
- LIVER
Greatly enlarged hepatocytes with homogeneous cytoplasm often containing large, eosinophilic droplets which had a laminary structure, variations in size and chromatin pattern of hepatocytic nuclei, an increased number of binucleated cells, necrosis of individual parenchymal cells, and slight proliferation of bile ducts ("oval cells") were regularly seen in the livers of the surviving animals at the 1 % level of feeding. At 0.2 % the hepatic change only consisted of slightly homogeneous cytoplasm and nuclei which varied slightly in size. At the lowest dosage level the livers were morphologically indistinguishable from those of the controls.
-THYROID
An activated appearance of the thyroid gland was seen in most of the male and female rats of the control group and of the various test groups. Degree and/or frequency of this "morphological activation" increased, however, with increasing levels of the test substance. Moreover, in a few rats of the two highest dose-groups papillary infoldings of the follicular epithelium occurred, which resulted in a thyroid picture similar to that in rats given thyroid-stimulating hormone (TSH). This finding shows that the test substance has a goitrogenic effect in rats. Signs of this effect were visible already at the lowest dosage level of 0.04 %.
Less important than the above mentioned changes in liver and thyroid, but (at least indirectly) compound-related abnormalities were observed in kidney (fatty infiltration, pigmentation, cystic tubules), male and female genital organs (atrophic changes), lung (edema and emphysema), stomach (hyperkeratosis), adrenal (fatty "vacuoles", hyperaemia and distended sinusoids), bone marrow (hypoplasia) and submaxillary salivary gland (increased ratio ducts: acini). The abnormeilities in these organs were seen only at the highest dose level and they may partly or completely be ascribed to inanition, except for the degenerative changes in the gonads which occurred also in a few males at 0.2 %. Additional histopathological changes occurred only in a single animal or were about equally distributed between the control group and the various test groups. Most of these lesions are, moreover, quite common findings in the strain of rats used. They may, therefore, not be attributed to the ingestion of the test material.
From gross and microscopic pathological examination it appears that 1 % of the test substance in the diet induced distinct lesions in a range of organs. Feeding of 0.2 % of the test article resulted in slight changes in liver, thyroid and testicle, whereas at the lowest dietary level of 0.04 % the only relevant finding was a slightly more activated appearance of the thyroid as compared with controls.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 0.04 other: % in food
- Sex:
- male/female
- Basis for effect level:
- other: morphological thyroid activation, hepatocellular changes and testicular alterations in the intermediate dose group
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- In a 90 day oral feeding study with rats, the NOEL is below 0.04 % per day. However, since the thyroid effect is known to be a rat-specific response to inductive processes in the liver, the NOAEL can be set at 0.04%.
- Executive summary:
In a 90 day oral feeding study, the test article was administered continuously at dosing levels of 0.04, 0.2 and 1 % in the diet to young albino Wistar rats. At a dietary level of 1%, serious ill effects as shown by mortality, considerable growth retardation and increased SAP levels were induced. Microscopically, hepatocellular hypertrophy accompanied by eosinophilic droplets in the cytoplasm, variations in the size of nuclei and increased numbers of mitotic figures as well as single cell necrosis and proliferation of bile ducts were observed in high dose rats. Additional histopathological findings in high dose rats were: fatty infiltration and pigmentation in renal epithelial cells, hyperkeratosis in the stomach, adrenal fatty changes, bone marrow hypoplasia and an increased ratio of ducts versus acini in the submaxillary gland and atrophic changes in the male and female reproductive organs. At a level of 0.2 % the major abnormalities were increased relative weights of livers and thyroids which were attended with histological changes. Testicular alterations were also observed in the intermediate group. At the lowest feeding level of 0.04 % slight differences with the control group were revealed only by the thyroid which showed an increased relative weight in males and histological differences with the controls in both sexes. The increased weight of this organ in males might be an incidental finding because the thyroid weight of male controls was low in comparison with that of control males in other sub-chronic studies. However, microscopically the thyroids of the 0.04 % group showed a slightly more activated appearance than did the control thyroids in both sexes. The NOEL is therefore below 0.04 %. However, since the thyroid effect is known to be a rat-specific response to inductive processes in the liver, the NOAEL can be set at 0.04%.
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