Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 204-040-1 | CAS number: 114-07-8
- 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:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- March 8, 1985 to July 17, 1985
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Per protocol and GLP.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 985
- Report date:
- 1985
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- yes
Test material
- Reference substance name:
- Erythromycin
- EC Number:
- 204-040-1
- EC Name:
- Erythromycin
- Cas Number:
- 114-07-8
- Molecular formula:
- C37H67NO13
- IUPAC Name:
- 6-{[4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-7,12,13-trihydroxy-4-[(5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy]-3,5,7,9,11,13-hexamethyloxacyclotetradecane-2,10-dione (non-preferred name)
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- rat
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source:Charles River Breeding Laboratories
- Age at study initiation:4 weeks old upon arrival and about 6 weeks old at the start of treatment.
- Fasting period before study: not noted
- Housing: throughout the study, animals were housed individually in hanging metal, mesh-bottom ca ges equipped with feeders and automatic waterers.Animal cages, racks and cage mats were changed regularly.The animal room was cleaned regularly .
- Diet (e.g. ad libitum): Certified Rodent Chow® pellet; were available ad libitum, except as noted elsewhere in this protocol.
Water (e.g. ad libitum): tap water were available ad libitum, except as noted elsewhere in this protoc ol.
- Acclimation period: 8days
ENVIRONMENTAL CONDITIONS
- Temperature (°C):. Ambient temperature was maintained at 72 ± 5°F.
- Humidity (%):Temperature and humidity were monitored continuously with a temperature-h ygrometer unit.
- Air changes (per hr): not noted
- Photoperiod (hrs dark / hrs light):The room was on a 14-hour daily light cycle.
Racks within the room were rotated 180° and moved one rack space within the room each week. IN-LIFE DATES: - March 8, 1985 (day 0) through April 11, 1985
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: saline in 0.2% hydroxypropylmethylcellulose.
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
To - Vehicle control
Tl -15.0 mg/kg/day, as free base . T2 -37.5 mg/kg/day, as free base. T3 -75.0 mg/kg/day, as free base. T4 - 150.0 mg/kg/day, as free base.
VEHICLE
- Concentration in vehicle:10 ml/kg.
- Amount of vehicle (if gavage):10 ml/kg. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Assayed values for samples of dosing formulations for all groups sent to Analytical Research for ana lysis during the first, fourth and twelfth weeks of the study corresponded closely to the theoretical values. In addition, assayed values of samples of both lots of bulk drug anayzed after the treatment period corresponded closely to the theoretical values.
- Duration of treatment / exposure:
- Each surviving rat received an oral dose by gavage each morning, seven days per week, for a period of approximately one or three months. During the treatment period each rat received a dose volume of 10 ml/kg based upon the most recent body weight data available.
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 15 mg/kg bw/day (actual dose received)
- Remarks:
- T1
- Dose / conc.:
- 37.5 mg/kg bw/day (actual dose received)
- Remarks:
- T2
- Dose / conc.:
- 75 mg/kg bw/day (actual dose received)
- Remarks:
- T3
- Dose / conc.:
- 150 mg/kg bw/day (actual dose received)
- Remarks:
- T4
- No. of animals per sex per dose:
- Two hundred and sixty-three Crl:Co®(SD)BR rats (132 males, 131 females)
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:The acute oral LD50 of ABBOTT-56268 in rats is reported to be in excess o f 5 g/kg.Two preliminary 30-day male rat oral toxicity studies were conducted by Taisho Pharmaceuti cal Co., Ltd. (Tokyo). The apparent "no-toxic-effect" dosage was 50 mg/kg/day . In the second preli minary rat study. The "no-toxic-effect" dosage was 75 mg/kg/day.
The lowest dosage (15 mg/kg/day) approximated the anticipated human clinical dosage, while the highest dosage (150 mg/kg/day) represented a dosage which had previously been shown to be toxic and was expected to be toxic when administered for one and three months. The intermediate dos ages represented approximately equal log intervals between the 15 and 150 mg/kg/day dosages. The oral route was used because this is an intended clinical route.
Rationale for animal assignment (if not random):random
Toxicology (D-468) personnel prepared the T1, T2, T3 and T4 formulations daily.Stability data showed that 1.44 to 49.8 mg/ml concentrations of ABBOTT-56268 in 0.2% hydroxypropylmeth ylcellulose
were stable for up to 7 days. - Positive control:
- None noted
Examinations
- Observations and examinations performed and frequency:
- All rats were observed twice each day during the pretreatment and treatment periods for survival and general condition. In addition to the above twice daily observations, further examinations of physical condition and behavior were recorded approximately 2-4 hours after dosing five days each week during the 3-month treatment period.
Body weight and food consumption were measured twice during the pretreatment period and twice weekly during the first four weeks of treatment and weekly thereafter.
Ophthalmoscopic examinations (funduscopic and slit lamp) were performed by a veterinarian on each rat prior to treatment initiation, during the fourth treatment week, and at the end of the three-month treatment period. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes
Anatomic Pathology
Eight rats (2 T0, 2 T1, 1 T2 and 3 T4) that died during the study were necropsied as soon as was p ractical.
The order in which the rats were necropsied was determined by a randomization schedule. The sched uled necropsies were conducted over several days.
Representative tissues from the organs listed below were assessed histologically from rats in groups To and T4 that were necropsied after three months of treatment as well as tissues from eight rats th at died during the treatment period.Because drug-related lesions were detected in the livers from the T4 rats, livers from the lower dosage groups were examined histologically.Other tissues from the T1
through T3 groups were however not examined microscopically, but were saved for future reference.
Adrenal
Aorta
Bone (vertebra)
Bone marrow (vertebra) Brain
Cecum Epididymis Esophagus Eye
Gross lesions (at discretion of the pathologist) Heart
Intestine, small Intestine, large
Kidney Liver Lung
Lymph node,
cervical Lymph node, mesenteric Lymph node, thoracic Mammary gland Ovary
Pancreas
Parathyroid
Peripheral nerve (sciatic) Pituitary
Prostate Rectum Salivary gland
Seminal vesicle Skeletal muscle Skin
Spinal cord Spleen Stomach Testis Thymus Thyroid Trachea
Urinary bladder
Uterus
Vagina - Other examinations:
- Organ Weights
Adrenals, brain, gonads, heart, kidneys and liver from each surviving rat were weighed at scheduled necropsy and the percent of body weight of each organ was calculated.
Urinalysis involved evaluation of the following parameters: Color
Turbidity
Glucose Ketones Specific gravity pH
Protein Bilirubin Occult blood
Microscopic sediment
Hematology
Red blood cell (RSC) count Erythrocytic indices Hematocrit
Hemoglobin
White blood cell (WBC) count Differential white blood]cell count Prothrombin time
Activated partial thromboplastin time
Clinical Chemistry Urea nitrogen Creatinine
Sodium Potassium Calcium Chloride Phosphorus
Alanine amino transferase (ALT) Aspartate amino transferase (AST) Alkaline phosphatase
Cholesterol Bilirubin Glucose Triglycerides Total protein Albumin
Globulin (calculated)
Albumin to globulin ratio (calculated) Gamma glutamyl transferase (GGT) - Statistics:
- Organ weight, body weight, food consumption and selected clinical pathology parameters were analyzed.T1, T2, T3 and T4 sex group means were compared to To sex group means and each otheusing analysis of variance and a suitable multiple comparison test. All statistical comparisons were performed at the
0.05 level of significance.
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
- Description (incidence and severity):
- the body weight gain of the group T1 males was statistically greater than that of the group T4 males.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased mean relative liver and kidney weights that exhibited dose-related tendencies for males.
- Gross pathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Treatment-related multinucleated hepato cytes of varying numbers were detected in the livers from t he mid-dose (37.5 and 75 mg/kg/day) and high-dose (150 mg/kg/day) rats
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY: Eight deaths occurred during the study: None of these deaths was considered to be treatment-related.
Clinical:
- Increased salivation occurred in both male and female drug-treated rats, with an apparent increase in frequency with time and dosage.
-Dehydration was observed with greater frequency with time in the drug-treated female rats, primarily in the groups T3 and T4 animals.
-Aggressive behavior was seen in both sexes in all groups, but sporadically and in a non-dose-relate d manner. Hyperactivity was observed in both sexes, primarily in the drug-treated groups and, in ge neral, at the higher dosages.
-Decreased activity occurred sporadically in the drug-treated rats of both sexes from the 42-55 day observation period.
-Urine-staining of the genital/anal areas occurred primarily in the group T4 female rats.
-Non-treatment- related signs included ptosis of the eyes, discharges, scabs, tinted hair, hair loss and abnormal teeth
BODY WEIGHT AND WEIGHT GAIN:
- Mean body weights of the T1 male rats were significantly greater than the group T0 males from day
20 through 59 (except day 52).
-Mean body weights of the T4 male rats were not significantly different from that o the To males on
any day. However, from day 31 onward, the mean weights of the T4 males were consistently lower th an those of the T0 males; this finding is considered to be of biological significance.
- From day 3 onward, the mean body weights of the group T1 males were statistically greater than that of the r4 males.
- The mean body weight gain of the T1 males over the 3-month treatment period was not statistically different from the group r0 males. However, the body weight gain of the group T1 males was statisti cally greater than that of the group T4 males.
-No significant differences were found among the mean body weights for female rats during the three- month treatment period.
FOOD CONSUMPTION: Food consumption in the T3 and T4 male and T4 female rats was significa ntly lower than in the T0 control rats, but only during isolated treatment periods.
- Food consumption in the T1 and T2 male rats was significantly higher than in the T0 control rats, but only during isolated treatment periods.Food consumption in the\T4 female rats was significantly less than in the T1 and To control rats on days 10-13.
- Thus, no consistent or dose-related pattern was seen in food consumption during the three-month treatment period.
OPHTHALMOSCOPIC EXAMINATION: - No ocular abnormalities, except for blepharitis in the right e ye of one rat which was not considered to be treatment related.
HAEMATOLOGY: No toxicologically significant differences between ABBOTT-56268-treated and control rats for hematologic parameters evaluated.
CLINICAL CHEMISTRYNo toxicologically significant differences between ABBOTT-56268-treated and control rats for clinical chemistry parameters evaluated
URINALYSIS: No toxicologically significant differences between ABBOTT-56268-treated and control rats for urinalysis.
NEUROBEHAVIOUR: not evaluated.
ORGAN WEIGHTS: Increased mean relative liver and kidney weights that exhibited dose-related te ndencies for males.
GROSS PATHOLOGY: No comments
HISTOPATHOLOGY: NON-NEOPLASTIC: Treatment-related microscopic changes characterized by the presence of multinucleated cells (hepatocytes) were evident in the livers from T2 through T4 rats.The incidence and severity of the changes were greatest in the T4 males. -The incidence and a ppearance of the multinucleated hepatocytes in the mid-dose sex groups (T2 and T3) resembled the incidence and appearance in the T4 females
HISTORICAL CONTROL DATA (if applicable)
OTHER FINDINGS: Treatment-related multinucleated hepatocytes of varying numbers were detected in the livers from the mid-dose (37.5 and 75 mg/kg/day) and high-dose (150 mg/kg/day) rats."No-
toxic-effect" level was considered to be 15 mg/kg/day.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 15 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see remark
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- This final three-month report describes the findings from a group of 100 rats randomly selected for
final necropsy. Treatment-related multinucleated hepatocytes of varying numbers were detected in the livers from the mid-dose (T2 = 37.5 mg/kg/day and T3 = 75 mg/kg/day) and high-
dose (T4 = 150 mg/kg/day) rats.The "no-observed toxic-effect" level was considered to be 15 mg/kg/
day.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.