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EC number: 253-657-2 | CAS number: 37763-23-8
- 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:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- end on 28-NOV-1998
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: study performed according to OECD guideline and GLP
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 998
- Report date:
- 1998
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Methyl (R)-amino(4-hydroxyphenyl)acetate
- EC Number:
- 253-657-2
- EC Name:
- Methyl (R)-amino(4-hydroxyphenyl)acetate
- Cas Number:
- 37763-23-8
- Molecular formula:
- C9H11NO3
- IUPAC Name:
- methyl (2R)-2-amino-2-(4-hydroxyphenyl)acetate
- Details on test material:
- - Name of test material (as cited in study report): HPGM
- Molecular formula (if other than submission substance): C9H11NO3
- Structural formula attached as image file (if other than submission substance): see Fig.
- Substance type: monoconstituent substance
- Physical state: powder
- Stability under test conditions: Stable for at least 5 hours in propylene glycol
- Storage condition of test material: at room temperature, dry and in the dark
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source:
- Age at study initiation: Charles River, Sulzfeld, Germany
- Weight at study initiation: males 192-196 g, females 156-161 g (mean values of the groups)
- Fasting period before study: data not available
- Housing: Group housing o f 5 animals per sex per cage in stainless steel suspended cages with wire mesh floors. During activity monitoring, animals were individually housed overnight in Macrolon plastic cages with sterilised sawdust provided as bedding.
- Diet: free access to standard pelleted laboratory animal diet
- Water: Free access to tap-water
- Acclimation period: at least 5 days before start of treatment under laboratory conditions
ENVIRONMENTAL CONDITIONS
- Temperature: 21°C
- Humidity: 50%
- Air changes: approximately 15 air changes per hour
- Photoperiod: 12 hours artificial fluorescent light and 12 hours dark per day
IN-LIFE DATES:
- Treatment : 14 July 1998 to 10 August 1998
- Blood sampling : 11 August 1998
- Necropsy : 11 August 1998
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- propylene glycol
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Formulations (wlw) were prepared daily within 4 hours prior to dosing. Adjustment was made for specific gravity of vehicle.
Storage conditions: at ambient temperature
VEHICLE
- Justification for use and choice of vehicle: based on trial formulations performed at NOTOX
- Concentration in vehicle: data not available
- Amount of vehicle (if gavage): 5 mL/kg bw
- Purity: data not available - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of week 3 formulations were analysed to check stability, homogeneity (highest and lowest concentration) and accuracy of preparations (all concentrations). Analysis were performed by HPLC.
Test substance formulations in propylene glycol were noted as stable for at least 5 hours and formed a homogeneous suspension at the concentrations tested. Analysis of the accuracy of dose preparations revealed values within the range of 96% to 105% of nominal, which was considered to represent an acceptable level of accuracy for formulations of this type. - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Once daily, approximately the same time each day, 7 days per week
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 50, 200 and 1000 mg/kg bw
Basis:
other: nominal
- No. of animals per sex per dose:
- 5 males and 5 females per group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: dose levels were selected on the basis of a 5-day dose range finding study
- Rationale for animal assignment: randomisation - Positive control:
- not applicable
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once prior to start of treatment and on days 8, 15, 22 and 28, clinical sings were also performed outside the home cage in a standard arena.
- Cage side observations: data not available
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily
BODY WEIGHT: Yes
- Time schedule for examinations: on days 1, 8, 15, 22 and 28.
Food consumption: weekly
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: immediately prior to scheduled post mortem examination
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: all rats/sex/group
- Parameters checked in table 1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: immediately prior to scheduled post mortem examination
- Animals fasted: Yes
- How many animals: all rats/sex/group
- Parameters checked in table 1 were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during week 4 of treatment
- Dose groups that were examined: all animals
- Battery of functions tested: hearing ability, pupillary reflex, static righting reflex, grip strength - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 2). All animals surviving to the end of the observation period were deeply anaesthetised using ether vapour and subsequently exsanguinated. All animals assigned to the study were necropsied and descriptions of all macroscopic abnormalities recorded.
HISTOPATHOLOGY: Yes (see table 2) - Other examinations:
- no
- Statistics:
- The following statistical methods were used to analyse the data.
Univariate one-way analysis of variance was used to assess the significance of intergroup differences.
If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
The Steel-test (many-to-one rank test) was applied when the data could not be assumed to follow a normal distribution.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance.
Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables.
Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations may have been rounded off before printing. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- see details below
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- see below
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY:
No mortality occurred during the study period.
Hunched posture was noted in one female treated at 1000 mg/kg/day from day 19 onwards. In addition, red staining of the skin on head or neck were noted in this female and three other females of this dose group.
Incidental findings that were noted included salivation, alopecia and brown staining of the skin. These findings were considered to be within the range of biological variation for rats of this age and strain.
BODY WEIGHT AND WEIGHT GAIN:
Body weights and body weight gain of treated animals remained in the same range as controls over the 4-week study period.
HAEMATOLOGY:
Haematological parameters of treated rats were considered not to have been affected by treatment.
CLINICAL CHEMISTRY:
There were no differences noted between control and treated rats that were considered to be related to treatment with HPGM.
NEUROBEHAVIOUR:
No abnormalities were observed in the functional observation tests. The variation in motor activity did not indicate a relation with treatment. The
values for motor activity in control males were slightly low when compared to historical data.
An extremely increased motor activity was noted in one male and six females. In the absence of a dose-dependent relationship this was considered to have occurred by chance without any toxicological relevance.
ORGAN WEIGHTS:
Liver : body weight ratios were increased in males and females treated at 1000 mg/kgd/da y. Kidney weights and kidney : body weight ratios were increased in males of this dose group only.
Statistically significant changes between heart weights of control and 200 mg/kg/day treated females were considered not to be a sign of toxicity since no dose response relationship or any corroborative findings in the other animals were detected.
GROSS PATHOLOGY:
Macroscopic observations at necropsy did not reveal any alterations that were considered to have arisen as a result of treatment.
HISTOPATHOLOGY: NON-NEOPLASTIC
Midzonallcentrilobular hypertrophy was recorded at a minimal or slight degree in four males and one female of the 1000 mg/kg/day dose group. This alteration was accompanied in females by an increased incidence of minimal or slight hepatocellular vacuolation.
The remainder of microscopic findings were within the range of background pathology encountered in Wistar rats of this age and strain and occurred at similar incidences and severity in both control and treated rats.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: The observed changes were only minimal in severity, did not indicate clear organ dysfunction or can be described as an adaptive response to the test substance.
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- From the results presented in this report a No Observed Adverse Effect Level (NOAEL) of 1000 mg/kg/day was concluded, since the observed changes were only minimal in severity, did not indicate clear organ dysfunction or can be described as an adaptive response to the test substance.
- Executive summary:
In a subacute toxicity study (OECD 407, GLP), HPGM was administered to Wistar rats (5/sex/dose level) by gavage at dose levels of 0, 50, 200 and 1000 mg/kg bw/day for 28 days.
The following parameters were evaluated: clinical signs daily; functional observation tests; body weight and food consumption weekly; clinical pathology and macroscopy at termination; organ weights and histopathology on a selection of tissues.
Results:
No treatment-related findings noted at 50 and 200 mg/kg bw/day.
At 1000 mg/kg bw/day:
- Hunched posture and red staining of the skin noted in females,
- Increased 1iver:body weight ratios noted in males and females. Increased kidney weights and kidney:body weight ratios noted in males,
- Hepatocellular hypertrophy observed in males and females, accompanied in females by hepatocellular vacuolation.
Conclusion:
From the results presented in this report a No Observed Adverse Effect Level (NOAEL) of 1000 mg/kg/day was concluded, since the observed changes were only minimal in severity, did not indicate clear organ dysfunction or can be described as an adaptive response to the test substance.
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