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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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- August 22, 1985 to Febrauary 13, 1986
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Segment II study conducted to GLP- adequate and acceptable for development endpoint.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 986
- Report date:
- 1986
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Principles of method if other than guideline:
- The purpose of this study was to re-evaluate the embryolethal and teratogenic potentials of ABBOTT-56268 following daily oral administration to pregnant rats during the period of major organogenesis.
- 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:
- other: Crl:Cn@(SD)BR rats
- Details on test animals or test system and environmental conditions:
- Crl:Co® (SD)BR rats were used because this is the strain in which a small number of cardiovascular abnormalities were noted among fetuses whose dams were exposed to 150 mg/kg/day of ABBOTT-5
6268.
TEST ANIMALS
- Source:Charles River Laboratories. sperm-positive female Crl:co®(SD)BR rats,2 bred by the suppl ier and shipped so as to arrive prior to gestation day 6
-
- Fasting period before study:
- Housing:housed in individual stainless steel hanging cages
- Diet (e.g. ad libitum):Certified Rodent Chow® #50023
- Water (e.g. ad libitum): yes tap water
- Acclimation period:
ENVIRONMENTAL CONDITIONS
- Temperature (°C): in a temperature- regulated (72 ± 5°F) room.Temperature and humidity were continuously monitored.
- Photoperiod (hrs dark / hrs light): The room was on a 14-hour daily light cycle. IN-LIFE DATES: August 22, 1985 through September 7, 1985
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.2% hydroxypropylmethylcellulose
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Rats in groups T1, T2 and T3 received ABBOTT-56268 suspended in 0.2% hydroxypropylmethylcellulose . Animals in the T0 group received the suspending medium only.Personnel in D-468 prepared the T1, T2, T3 formulations once each week.
VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 0.2%
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):
- Purity: - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of dosing formulations for groups T0-T4 were sent to D-417 (PPD Analytic Research) for analysis of ABBOTT- 56268 concentrations.
Assay results for the submitted ABBOTT-56268 formulations were within 2-3% of theoretical in all cases. - Duration of treatment / exposure:
- day 6 of gestation to day 20 of gestation.
- Frequency of treatment:
- Administered once each day by gavage
- Duration of test:
- treatment dates. August 22, 1985 through September 7, 1985.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 15 mg/kg bw/day (nominal)
- Remarks:
- Basis:
analytical conc.
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Remarks:
- Basis: analytical conc.
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- Remarks:
- Basis: analytical conc
- No. of animals per sex per dose:
- 20 females per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- All animals were observed at least twice daily (approximately 1-2 and 24 hours post-treatment) durin g the treatment period for signs of altered behavior or physical condition. Once treatment was susp
ended single daily observations were instituted. Body weights were recorded on gestational days 6, 9,
12 and 15 and once again just prior to laparotomy on
gestational day 20. Food consumption was measured for gestational days 6- 9, 9-12 and 12-15. Any animal that died was examined by a pathologist
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed at least twice daily (approximately 1-2 and 24 hours po st-treatment) during the treatment period for signs of altered behavior or physical condition. Once treatment was suspended single daily observations were instituted
DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule: All animals were observed at least twice daily (approximately 1-2 and 24 hours p ost-treatment) during the treatment period for signs of altered behavior or physical condition. Once treatment was suspended single daily observations were instituted
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded on gestational days 6, 9, 12 and 15 and once again just prior to laparotomy on
gestational day 20.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes. Food consumption was measured for gestational days 6- 9, 9-12 and 12-15.
- 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: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: All fetuses were then delivered by abdominal section, sexed, weighed and examined for grossly visible external abnormalities. Number and uterine positions of live and dead fetuses, resorptions, degenerating fetuses and any abnormalities were recorded
OTHER: All fetuses were then processed for further evaluation.All specimens were placed in Bouin
's Solution and were allowed to stand for one to several weeks to permit decalcification, then were examined for visceral defects. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:
Number and uterine positions of live and dead fetuses, resorptions, degenerating fetuses and any abnormalities were recorded. - Fetal examinations:
- - External examinations: Yes: [all per litter }
- Soft tissue examinations: Yes: [all per litter)
- Skeletal examinations: Yes: [all per litter
- Head examinations: No data - Statistics:
- Data pertaining to maternal body weight and food consumption, fetal weights, sex ratios, resorbed embryos and degenerate fetuses, litter size and fetal abnormalities were summarized.Appropriate statistical evaluation (as determined by Nonclinical Statistics) was performed as needed. All statistica
l tests were performed at the 0.05 level of significance. - Historical control data:
- Due to the extreme rarity of such abnormalities among concurrent or historical controls, even this l ow level of cardiovascular abnormalities must be judged to be drug-related. The absence of serious abnormalities in a study performed at comparable doses in another strain of rat (Slc:Wistar) points to the possibility that these adverse developmental findings may be strain specific.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Maternal deaths and treatement related observations:One control animal died as a result of an int ubation accident; all other animals survived.
Overt clinical signs were not evident. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight gain and food consumption were adversely affected at the 150 mg/kg/day dose of ABB OTT-56268.
Lesser effects on both parameters at the 50 mg/kg/day dose of ABBOTT-56268 and no effect at 15 mg/kg/day dose.
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes. Remark: body weight
Maternal deaths and treatement related observations:One control animal died as a result of an int ubation accident; all other animals survived.
Overt clinical signs were not evident.
Body weight gain and food consumption were adversely affected at the 150 mg/kg/day dose of ABB OTT-56268.
Lesser effects on both parameters at the 50 mg/kg/day dose of ABBOTT-56268 and no effect at 15 mg/kg/day dose.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 50 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): No statistically significant differences, but mean weight of T3 (150 mg/kg/day, ABBOTT-
56268)fetuses was slightly reduced compared with controls. - External malformations:
- not specified
- Description (incidence and severity):
- The only serious grossly visible abnormalitywas a markedly reduced lower jaw
10 a T2 (50 mg/kg, ABBOTT-56268) fetus. Superficial hematomas were noted among 3 T0, 2 T1 and
1 T3 fetuses. - Visceral malformations:
- not specified
- Description (incidence and severity):
- .A statistically significant increasing trend in incidence of undescended testes among ABBOTT-56268-treated groups was noted.In terms of incidence this was O T0, 0 T1, 1 T2 and 2 T3 fetuses.No biological significance is attributed to these small differences.
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes. Remark: A low level of major cardiovascular abnormalities was found rat fetuses following oral administration at 150 mg/kg/day.This dosage was maternally toxic as well. No significant developmental effects were noted at a dosage of 50 mg/kg/day.
Details on embryotoxic / teratogenic effects: Embryolethality: no effect
Feta weights: No statistically significant differences, but mean weight of T3 (150 mg/kg/day, ABBOTT-
56268)fetuses was slightly reduced compared with controls.
Fetal Development: Incidence of major malformations was quite low; however, the few cardiovascular abnormalities noted (3 abnormal fetuses in 2 litters), were confined to the T3 (150 mg/kg/day) group.
Gross Abnormalities.The only serious grossly visible abnormalitywas a markedly reduced lower jaw
10 a T2 (50 mg/kg, ABBOTT-56268) fetus. Superficial hematomas were noted among 3 T0, 2 T1 and
1 T3 fetuses.
Visceral Findings.A statistically significant increasing trend in incidence of undescended testes among ABBOTT-56268-treated groups was noted.In terms of incidence this was O T0, 0 T1, 1 T2 and 2 T3 fetuses.No biological significance is attributed to these small differences.
Effect levels (fetuses)
- Remarks on result:
- not determinable
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The incidence of major cardiovascular malformations was very low in this study.However, the 3 affected fetuses (from 2 litters) were in the T3 (150 mg/kg, ABBOTT-56268) group. This dosage wa s maternally toxic as well. Due to the extreme rarity of such abnormalities among concurrent or his
torical controls, even this low level of cardiovascular abnormalities must be judged to be drug-related. The absence of serious abnormalities
in a study performed at comparable doses in another strain of rat (Slc:Wistar) points to the possibility that these adverse developmental findings may be strain specific.
No significant developmental effects were noted at a dosage of 50 mg/kg/day.
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