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EC number: - | CAS number: -
- 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:
- 11 July - 16 August 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
- Report date:
- 2013
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Test material form:
- liquid: viscous
- Details on test material:
- - Name of test material (as cited in study report): 4,4’-Isopropylidenediphenol, oligomeric reaction products with 1-chloro-2,3-epoxypropane, reaction products with butan-1-ol and 3-aminomethyl-3,5,5-trimethylcyclohexylamine
- Substance type: Clear colourless viscous liquid
- Physical state: liquid
- Purity: 100% (UVCB)
- Lot/batch No.: WA 522
- Expiration date of the lot/batch: 01 January 2014
- Storage condition of test material: At room temperature in the dark
- Purity/composition correction factor required No
- Hygroscopic No
- Reactivity: Reactive to moisture
- Test substance handling: No specific handling required
- Density: 1.02 g/cm3 (20°C)
- Stability in vehicle Polyethylene glycol: Not indicated
- Solubility in vehicle Polyethylene glycol: Not indicated
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Source: Charles River Deutschland, Sulzfeld, Germany..
- Age at study initiation: Young adult animals. Approximately 6 weeks (control and 500 mg/kg) or approximately 7 weeks (150 and 1000 mg/kg.
- Weight at study initiation: Body weight variation was within +/- 20% of the sex mean (males: 149 - 218 grams; females: 118 - 166 grams).
- Housing: Group housing of 5 animals per cage in labeled Macrolon cages
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water.
- Acclimation period: At least 5 days
ENVIRONMENTAL CONDITIONS
Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, approximately 15 room air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.
Deviations from the daily mean relative humidity occurred. Evaluation: Laboratory historical data do not indicate an effect of the deviations.
IN-LIFE DATES: From: 11 July - 16 Augustus 2012
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenized to a visually acceptable level. Adjustment was made for specific gravity of the vehicle and the density of the test substance. No correction was made for the purity of the test substance.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on trial formulations performed at WIL Research Europe and on information from the sponsor.
DOSE VOLUME:
5 mL/kg body weight. Actual dose volumes were calculated weekly according to the latest body weight. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- No chemical analysis of formulations were performed in the 28-day range finding study.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Once daily, 7 d/w.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 150, 500, 1000 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 3
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
Dose level of group 2 is based on an acute oral toxicity study (Project 500254). Dose levels of group 3 and 4 were amended based on the results of group 1 and 2.
Initially all animals at 500 mg/kg were dosed too low on 09 August 2012. The additional amount was administered short after (within maximally 20 minutes).
Evaluation: The dose levels were correct after the additional amount was administered. Dosing twice on one day occurred only once and is considered not to have affected the study results. - Positive control:
- Not required.
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS:
- Time schedule: At least twice daily. Animals showing pain, distress or discomfort, which was considered not transient in nature or was likely to become more severe, were sacrificed for humane reasons based on OECD guidance document on humane endpoints (ENV/JM/MONO/ 2000/7). The time of death was recorded as precisely as possible.
DETAILED CLINICAL OBSERVATIONS:
- Time schedule: At least once daily from start of treatment onwards, detailed clinical observations were made in all animals, at 0-15 minutes, 1 hour (±15 minutes) and 3 hours (± 30 minutes) after dosing. The time of onset, grade and duration of any observed signs were recorded.
BODY WEIGHT:
- Time schedule for examinations:Weekly.
FOOD CONSUMPTION:
- Weekly.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day
FOOD EFFICIENCY: yes
WATER CONSUMPTION: No
- Subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected.
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: immediately prior to scheduled post mortem examination
- Anaesthetic used for blood collection: isoflurane
- Animals fasted: yes
- How many animals: all animals
- Parameters checked: According to test guidelines
CLINICAL CHEMISTRY: Yes / No / No data
- Time schedule for collection of blood: immediately prior to scheduled post mortem examination
- Anaesthetic used for blood collection: isoflurane
- Animals fasted: yes
- How many animals: all animals
- Parameters checked: According to test guidelines
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
- All animals were fasted overnight with a maximum of 24 hours prior to planned necropsy, but water was provided. Animals surviving to scheduled necropsy and all moribund animals were deeply anaesthetised and subsequently exsanguinated.
- Dose groups that were examined: all groups
- Tissues/organs checked: According to test guidelines
ORGAN WEIGHTS: Yes
Organs checked according to test guidelines.
HISTOPATHOLOGY: Yes
According to test guidelines
No terminal body weight was determined in females at 150 mg/kg.
Evaluation: Although relative organ weights cannot be determined in this study, sufficient information is available for interpretation of the results of this study. - Statistics:
- A descriptive statistical analysis was performed (mean, SD, median).A descriptive statistical analysis was performed (mean, SD, median).
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):
- effects observed, treatment-related
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Description (incidence and severity):
- Based on subjective appraisal.
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- MORTALITY AND CLINICAL SIGNS
- All rats treated at 1000 mg/kg died spontaneously or were killed moribund on Days 4 and 6 of the study. No mortality occurred in other dose groups.
- At 1000 mg/kg the following clinical signs were noted during the observation period prior to death:
Lethargy, hunched posture, abnormal gait, rales, swelling of the abdomen, piloerection, chromodacryorrhoea on the snout, pale or dehydrated appearance, ptosis, yellow urine and/or hypothermia.
All animals at 500 mg/kg showed hunched posture and piloerection. The males at this dose levels showed additionally lethargy, laboured respiration, rales and ptosis during the observation period.
Piloerection was noted in males at 150 mg/kg on several days during the observation period.
No clinical signs of toxicity were noted in females at 150 mg/kg and control animals.
The slight degree of salivation shown among the animals at 150, 500 and 1000 mg/kg is often noted in rats of this age and strain following oral gavage and may be related to irritant properties or taste of the test substance. Therefore salivation was not considered to be of toxicological relevance.
BODY WEIGHT AND WEIGHT GAIN
Body weights in males at 500 mg/kg are considered to be slightly lower than controls over the 4-week study period. Body weights from animals treated at 150 mg/kg were within the normal range of variation for this strain and comparable to the control animals.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
In accordance with slightly lower body weights in males treated at 500 mg/kg, food consumption in these animals is considered to be slightly lower than controls over the 4-week study period. No effects on food consumption were noted in animals treated at 150 mg/kg.
HAEMATOLOGY
The following changes in haematology parameters distinguished animals at 500 mg/kg from control animals. Although the changes are within normal range levels encountered for rats of this age and strain these findings together suggest a toxicological relevance:
• Higher reticulocyte count females
• Lower heamoglobin level in females
• Lower heamatocrit level in males and females
• Lower mean corpuscular volume (MCV) in females
• Higher mean corpuscular haemoglobin concentration (MCHC) in males
• Higher platelet count in males and females
• Higher prothrombin time (PT) in males
• Lower activated partial thromboplastin time (APTT) in males and females
All values in animals treated at 150 mg/kg remained in the range expected for rats of this age and strain.
CLINICAL CHEMISTRY
The following changes in clinical biochemistry parameters distinguished animals at 500 mg/kg from control animals and from normal range levels encountered for rats of this age and strain:
• Higher alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) in males and females
• Lower total protein and albumin levels in males and females
• Lower glucose level in males
All other values in the animals treated at 500 mg/kg and all values in animals treated at 150 mg/kg remained in the range expected for rats of this age and strain.
ORGAN WEIGHTS
No toxicological relevant changes were noted in absolute and relative organ weights in animals treated at 150 and 500 mg/kg.
Heart, thymus and spleen weight appeared to be lower in males at 500 mg/kg compared to normal. However, the organ:body weight ratios of these organs were considered to be similar to those of control animals. Therefore this was considered to be related to the lower body weights.
No relative organ weights could be calculated in females at 150 mg/kg. Despite the missing information, sufficient information is available for evaluation of the absolute and relative organ weights.
GROSS PATHOLOGY
Necropsy at the end of the observation period did not reveal any toxicologically relevant alterations in animals at 150 and 500 mg/kg.
The animals treated at 1000 mg/kg, which were all found death or sacrificed in moribund condition, showed advanced autolysis, discolouration of the stomach, foci in the stomach, gelatinous contents of the small intestines and caecum and/or reduced size of the thymus.
HISTOPATHOLOGY
There were minor treatment-related microscopic findings in the liver of animals at 500 mg/kg. These findings included: minimal single cell necrosis in one male and one female, minimal micro-vesicular vacuolation in one female and minimal increased severity of inflammatory cell foci, lymphocytic (noted in all animals at grades minimal up to slight).
No treatment related findings were present in the livers of the animals at 150 mg/kg.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 500 mg/kg bw/day (actual dose received)
- 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:
- Based on the changes seen in body weight gain, haematology and clinical biochemistry and
microscopic findings in the liver 4,4’-Isopropylidenediphenol, oligomeric reaction products with 1-
chloro-2,3-epoxypropane, reaction products with butan-1-ol and 3-aminomethyl-3,5,5-
trimethylcyclohexylamine is considered to induce toxicological changes at 500 and 1000 mg/kg.
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.

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