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EC number: 444-860-9 | CAS number: 474510-57-1
- 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:
- 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: well documented, according to OECD guideline and GLP
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
- Report date:
- 2012
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 444-860-9
- EC Name:
- -
- Cas Number:
- 474510-57-1
- Molecular formula:
- C21 H24 O4
- IUPAC Name:
- 2-hydroxy-1-(4-{[4-(2-hydroxy-2-methylpropanoyl)phenyl]methyl}phenyl)-2-methylpropan-1-one
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Source: Harlan Laboratories, B.V. Kreuzelweg 53 5961 NM Horst / Netherlands
- Age at study initiation: 11 weeks
- Weight at study initiation: Males: 291 to 371 g, Females: 182 to 213 g
- Housing: singly
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7d
- Fasting: 16h before administration
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
-The dose formulations were prepared weekly
- Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.
VEHICLE
- Justification for use and choice of vehicle (if other than water): As used in previous dose range-finding study - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The samples were analyzed following an analytical procedure provided by the Sponsor and
adapted at Harlan Laboratories. The test item was used as the analytical standard. Analyzed
samples were not discarded without written consent from the study director.
Duplicates were taken of all samples and were stored at Harlan Laboratories Ltd., Füllinsdorf /
Switzerland. The samples were not discarded without written consent from the study director. - Duration of treatment / exposure:
- Males: 4 weeks
Females: Approximately 7 weeks - Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
10, 30, 90 mg/kg bw
Basis:
actual ingested
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected based on a previous dose range-finding toxicity study in Han Wistar rats
- Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: daily
HAEMATOLOGY: Yes
- Time schedule for collection of blood: on the day of the scheduled necropsy from 5 males from each group, blood samples from 5 lactating females from each group were obtained on day 5 post partum
- Anaesthetic used for blood collection: Yes, isoflurane
- Animals fasted: Yes, 18h
- How many animals: 5 per sex and group
- Parameters checked in table [1] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on the day of the scheduled necropsy from 5 males from each group, blood samples from 5 lactating females from each group were obtained on day 5 post partum
- Animals fasted: Yes, 18h
- How many animals: 5 per sex and group
- Parameters checked in table [2] were examined.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: one time during the study
- Dose groups that were examined: 5 animals per sex and group
- Battery of functions tested: cage side observations, hand-held observations, open field observations, reflexes, hind / fore limb strength - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table) - Statistics:
- The Dunnett-test (many to one t-test) based on a pooled variance
estimate was applied if the variables could be assumed to follow a normal distribution
for the comparison of the treated groups and the control groups for each sex.
• The Steel-test (many-one rank test) was applied instead of the
Dunnett-test when the data could not be assumed to follow a normal distribution.
• Fisher's exact-test was applied if the variables could be
dichotomized without loss of information.
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
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- effects observed, treatment-related
- 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):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
At 90 mg/kg body weight/day, one male was killed for ethical reason, relationship to the treatment could not be excluded.
Test item-related clinical signs were observed of males and females receiving 90 mg/kg body weight/day. Hunched posture, ruffled fur and discoloured feces were seen in the pre-pairing and pairing period in males and in the pre-pairing, through pairing and gestation period in females.
BODY WEIGHT AND WEIGHT GAIN
The mean body weight gain of males receiving 90 mg/kg body weight/day was lower from day 5 of pre-pairing period when compared to controls and it was statistically significantly reduced between days 8 and 14. In correlation with the low food consumption this was considered to be a test item-related effect.
FOOD EFFICIENCY
The mean food consumption of males receiving 90 mg/kg body weight/day was statistically significantly lower on the second week of pre-pairing period, and for females during the whole pre-pairing period. This was considered to be a test item-related effect.
NEUROBEHAVIOUR
A slightly lower locomotor activity of the high dose group was seen, thus a treatment-related effect can not be excluded. For females at the dose level of 90 mg/kg body weight/day, total level of locomotor activity was statistically significantly reduced.
ORGAN WEIGHTS
Absolute and relative mean liver weights (both relative to body weight and relative to brain weight) were statistically increased in males and females of group 4 (90 mg/kg body weight/day). Additionally, absolute and relative mean thymus weights were statistically significantly decreased in females of the 90 mg/kg body weight/day group.
GROSS PATHOLOGY
Treatment-related adverse local irritative effects in the stomach were observed in all test item-treated groups at incidences of 1, 2 and 2 animals at the dose levels 10, 30 and 90 mg/kg body weight/day, respectively.
The reduced size in thymus in females, occurring in increased incidences, at ≥ 10 mg/kg body weight/day correlated histopathologically with athropy and reduced absolute and relative thymus weights only at the high dose levels. Although this is considered to be most likely to be stress related a test item-relationship cannot be excluded at the 90 mg/kg body weight/day dose level.
HISTOPATHOLOGY: NON-NEOPLASTIC
Treatment-related diffuse liver cell hypertrophy at 90 mg/kg body weight/day was considered to be adaptive. This hypertrophy was associated with follicular cell hypertrophy in thyroid glands in some males and females at 90 mg/kg body weight/day. Most probably the enhanced liver cell metabolism resulted in an acceleration of thyroid hormone breakdown with consequent thyroid follicular cell hypertrophy. This finding is commonly seen in rats after being exposed to xenobiotics.
HISTORICAL CONTROL DATA (if applicable)
historical dat (up to 23 studies) for FOB, breeding, organ weights, organ/BW and organ/brain ratios
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 30 mg/kg bw/day (actual dose received)
- Sex:
- male/female
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
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.
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