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EC number: 605-092-1 | CAS number: 157248-25-4
- 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:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Aug 07, 2012 - Feb 20, 2013
- Reliability:
- 1 (reliable without restriction)
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- 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)
- Version / remarks:
- adopted October 03, 2008
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 4'-ethyl-2,3-difluoro-4-(4-propylphenyl)-1,1'-biphenyl
- EC Number:
- 605-092-1
- Cas Number:
- 157248-25-4
- Molecular formula:
- C₂₃H₂₂F₂
- IUPAC Name:
- 4'-ethyl-2,3-difluoro-4-(4-propylphenyl)-1,1'-biphenyl
- Test material form:
- solid: bulk
Constituent 1
- Specific details on test material used for the study:
- Purity: >99.90%
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- Species: Rat
Strain: Crl: WI (Han)
Breeder: Charles River, Germany - Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Germany
- Age at study initiation: 8w
- Weight at study initiation: 233 (m), 165 (f)
- Fasting period before study: no
- Housing: grouped
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 7 days
DETAILS OF FOOD AND WATER QUALITY:
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 1°C
- Humidity (%): 37 - 65 %
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 h / 12 h
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- The test item was administered orally by gavage, once daily, 7 times a week for 4 weeks.
The volume of administration was 5 mL/kg body weight. The volume of administration per
animal was calculated by means of the LIM-System. - Vehicle:
- other: 0.25% aqueous hydroxypropyl methylcellulose (Methocel® K4M Premium)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): lab standard vehicle
- Concentration in vehicle: 0.25% aqueous hydroxypropyl methylcellulose (Methocel® K4M Premium)
- Amount of vehicle (if gavage): 5 mL/kg
- Lot/batch no. (if required): -
- Purity: analytical grade - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The quantification of the test item in the dosing
formulations was performed using a HPLC method with UV
detection. During the course of the study each dosing formulation
(including control) of two preparations periods were sampled and
analyzed at the beginning and the end of usage, resulting in 4 time
points of formulation analysis. - Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- once daily, 7 times a week for 4 weeks
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 3 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 10 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 30 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 0 mf/kg: 20 (10 m/ 10 f)
3 mg/kg: 10 (5 m/ 5 f)
10 mg/kg: 10 (5 m/ 5 f)
30 mg/kg: 20 (10 m/ 10 f) - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: recovery
- Post-exposure recovery period in satellite groups: 2 weeks
- Section schedule rationale (if not random): random - Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- Clinical Signs
Mortality, the behavior and appearance of each animal were checked twice daily at
working days and once at off days, preferably at the same time (s) each day. Symptoms
were recorded with the LIM-System
Body Weight
Each rat was weighed before treatment and thereafter once a week. The parameter was
recorded with the LIM-System.
Food consumption
Food consumption was determined once a week by weighing the food per cage which had
not been consumed. The parameter was recorded with the LIM-System.
Gross Pathology
At the time scheduled the rats were anesthetized by a carbon dioxide air mixture and
exsanguinated by opening the abdominal vessels. They were necropsied and examined for gross
pathological alterations.
All findings were recorded with the LIM System.
Body and Organ Weights
The body and organs weights were recorded with the LIM-System. Based on the absolute organ
weights the relative organs weights (related to 100g body weight) were calculated. For all
animals the following weights were determined:
The following weights were determined:
Terminal body weight (after exsanguination)
Heart
Liver
Kidneys (together)
Spleen
Thymus
Testes (together)
Prostate
Uterus
Ovaries (together)
Adrenals (together after fixation)
Thyroids with Parathyroids (together after fixation)
Brain (after fixation)
Seminal vesicles
Epididymides (together)
Histopathology
The organs and tissues of main kill animals were fixed, histotechnically processed and examined
as listed below.
Main kill
Adrenal (2)
Aorta
Bone with knee joint (os femoris)
Bone with bone marrow (sternum, femur)
Brain (cerebrum, cerebellum, brain stem)
Esophagus
Eye (2)
Heart F
Intestine, large
Cecum
Colon
Rectum
Intestine, small
Duodenum
Jejunum
Ileum
Kidney (2)
Larynx
Liver (left lateral and right medial lobe)
Lung (with mainstem bronchi)
Lymph nodes
mandibular (2)
mesenteric
Mammary gland (inguinal)
Micro transponder
Muscle, skeletal (thigh)
Nasal turbinates
Nerve, optic (2)
Nerve, sciatic
Pancreas
Parathyroid (2)
Peyer’s Patches
Pituitary
Reproductive organs, female
Ovary (2)
Oviduct (2)
Uterus (cornu/corpus/cervix)
Vagina
Reproductive organs, male
Epididymis (2)
Prostate
Seminal vesicle
Testis (2)
Salivary gland (2)
(submandibular, parotid, sublingual)
Skin (inguinal)
Spinal cord (cervical, thoracal, lumbal)
Spleen
Stomach (proventricular, fundic, pyloric)
Thymus
Thyroid (2)
Tongue
Trachea
Ureter (2)
Urinary bladder
Zymbal's gland (2)
All tissues showing abnormalities
For recovery animals tissue fixation was performed as for the main kill group.
The adrenals, female reproductive organs (ovary, uterus, vagina) and pituitary were investigated
in all dose groups of the main kill and in recovery animals.
All histopathology findings were recorded with the LIM-System. - Sacrifice and pathology:
- The animals were necropsied, examined for gross pathological alterations, the weights of
selected organs were recorded and histotechnical procedures and histopathological examinations
were performed. - Statistics:
- All parameters were analyzed separately for each sex and time. To take the number of dose
groups into account, all the test procedures used maintain a multiple significance level of
alpha= 0.05.
Absolute body weight, body weight gain (differences to baseline values on day 0), food
consumption, and organ weights - relative and absolute - of the dose groups were
compared with those of the control, using the multiple two-sided Dunnett-Test (Dunnett
1955, 1964). When the parameters were compared in the recovery period between the
control (group 1) and high dose (group 4), the standard t-test (Winer, 1970) was used.
Software: Body weight gain, food consumption and organ weights were evaluated within
the LIM-System.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No treatment-related clinical signs, changes of body weight, and body weight gain were
observed in any dose group of both genders during the treatment and recovery period. - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food consumption was unchanged during the treatment period in both genders, and in
females during the recovery period. The males showed a slightly decreased food
consumption during the recovery period that is not considered biologically relevant. - Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- At necropsy only spontaneous alterations were observed. Toxicological relevant body or organ weight deviations were not observed in any dose group of
main kill or recovery animals. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- At histopathology examination the female rats of all groups exhibited cytoplasmatic vacuolation in the zona fasciculata of the adrenal gland. The males were not affected. There was a clear dose dependency
with regard to incidence and severity as one female at 3 mg/kg was affected to a mild degree; all females at 10 mg/kg showed a minimal to mild degree and all females at 30 mg/kg exhibited a moderate degree. The high dose recovery females showed a vacuolation of the zona fasciculata which was more pronounced than the main kill females as a moderate to massive degree was noted in all animals. Two females of the recovery group showed minimal to mild degeneration/ necrosis of inner cortical cells in addition.
In the ovary, minimal cytoplasmic vacuolation of interstitial cells was detected in one rat at 3 mg/kg, a mild degree was seen in four rats at 10 mg/kg and a moderate degree in all 5 rats at
30 mg/kg. In recovery animals at 30 mg/kg incidence and degree of cytoplasmic vacuolation of interstinal cells was consistent with the main kill animals at this dose. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Effect levels
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 30 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
Target system / organ toxicity
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 10 mg/kg bw/day (actual dose received)
- System:
- urinary
- Organ:
- adrenal glands
Applicant's summary and conclusion
- Conclusions:
- Daily oral administration of 3, 10, or 30 mg/kg of 4-Ethyl-2',3'-difluor-4''-propyl-1,1':4',1''-terphenyl to rats for 4 weeks was clinically tolerated with no mortality, clinical signs, changes of body weight, or
relevant changes of food consumption.
However, at histopathology, alterations in the adrenal gland and ovary in female rats were observed at all dose levels. Dose-dependent vacuolation in the adrenal cortex and
vacuolation of interstitial cells of the ovary were observed, at the low dose of 3 mg/kg one rat was affected. No signs of reversibility were discernable after the 2-week treatment free
period. The cytoplasmic vacuolation in the adrenal and ovary might reflect persistent metabolic changes due to impairment of steroidogenesis and/or retention of the xenobiotic.
Therefore, for the females a NOEL (no effect level) or NOAEL (no observed adverse effect level) could not be established. For the males, a NOEL could be established at 30
mg/kg under the conditions of this study. - Executive summary:
Objective
4-Ethyl-2',3'-difluor-4''-propyl-1,1':4',1''-terphenyli s an industrial chemical which needs to be registered in the European Union according to Annex VIII of the REACH regulation (>10-100 tons per annum). Such registrations require data on repeat dose toxicity, i.e. a subacute toxicity study in rats with oral administration.
Study Design
4-Ethyl-2',3'-difluor-4''-propyl-1,1':4',1''-terphenyl was administered orally by gavage, once daily, 7 times a week for 4 weeks to 3 groups of male and female Crl:WI (Han) rats at doses of 3, 10 or 30 mg/kg. A similarly constituted control group received the vehicle, 0.25% aqueous hydroxypropyl methylcellulose (Methocel® K4M Premium), and served to generate contemporary control data.
The control and high dose groups consisted of 10 male and 10 female rats each. The low dose and mid dose groups consisted of 5 male and 5 female rats each. At the end of the
treatment period, 10 (5 males and 5 females) rats were scheduled for necropsy. The remaining rats of groups 1 and 4 were scheduled for a 2-week recovery period. The rats
were gang-housed under conventional conditions.
All rats were subjected to macroscopic and histopathological examinations. Selected organs were weighed from each rat at the end of the treatment period.
Results
Formulation analysis revealed that the dose groups received the anticipated concentrations and no test material was detected in the control formulations.
All animals survived the treatment and recovery period.
No treatment-related clinical signs, changes of body weight, and body weight gain were observed in any dose group of both genders during the treatment and recovery period.
Food consumption was unchanged during the treatment period in both genders, and in females during the recovery period. The males showed a slightly decreased food
consumption during the recovery period that is not considered biologically relevant.
At necropsy only spontaneous alterations were observed. Body and organ weight determinations revealed no relevant deviations in any dose group of main kill or recovery
animals.
At histopathology the female rats of all dose groups (3, 10, and 30 mg/kg) exhibited a cytoplasmatic vacuolation in the zona fasciculata of the adrenal gland. Incidence and
severity were clearly dose-dependent as one female at 3 mg/kg was affected to a mild degree; all females at 10 mg/kg showed a minimal to mild degree and all females at
30 mg/kg exhibited a moderate degree. The males were not affected.
At the end of recovery, the high dose (30 mg/kg) females showed a moderate to massive vacuolation of the zona fasciculate. Severity was more pronounced in the main kill
females. Two females of the recovery group showed minimal to mild degeneration/necrosis of inner cortical cells in addition.
In the ovary, minimal cytoplasmic vacuolation of interstitial cells was detected in one rat at 3 mg/kg, a mild degree was seen in four rats at 10 mg/kg and a moderate degree in all 5
rats at 30 mg/kg. At the end of recovery, high dose (30 mg/kg) recovery animals had the same incidence and degree of cytoplasmic vacuolation of interstitital cells as the main kill
animals of this dose level.
Conclusions
Daily oral administration of 3, 10, or 30 mg/kg of 4-Ethyl-2',3'-difluor-4''-propyl-1,1':4',1''-terphenyl to rats for 4 weeks was clinically tolerated with no mortality, clinical signs, changes of body weight, or
relevant changes of food consumption.
However, at histopathology, alterations in the adrenal gland and ovary in female rats were observed at all dose levels. Dose-dependent vacuolation in the adrenal cortex and
vacuolation of interstitial cells of the ovary were observed, at the low dose of 3 mg/kg one rat was affected. No signs of reversibility were discernable after the 2-week treatment free
period. The cytoplasmic vacuolation in the adrenal and ovary might reflect persistent metabolic changes due to impairment of steroidogenesis and/or retention of the xenobiotic.
Therefore, for the females a NOEL (no effect level) or NOAEL (no observed adverse effect level) could not be established. For the males, a NOEL could be established at 30
mg/kg under the conditions of this study.
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