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EC number: 205-426-2 | CAS number: 140-66-9
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
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- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
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- Auto flammability
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- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
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- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
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- Endpoint summary
- Stability
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- 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:
- August - November 1981
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Comparable to guideline study OECD 408; individual animal were recorded but are not part of this study report
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 982
- Report date:
- 1982
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- : Higher number of animals used (20 per sex and dose; OECD recommends 10); no ophthalmological examination; sensory reactivity not examined separately.
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- 4-(1,1,3,3-tetramethylbutyl)phenol
- EC Number:
- 205-426-2
- EC Name:
- 4-(1,1,3,3-tetramethylbutyl)phenol
- Cas Number:
- 140-66-9
- Molecular formula:
- C14H22O
- IUPAC Name:
- 4-(2,4,4-trimethylpentan-2-yl)phenol
- Reference substance name:
- Isooctylphenol
- EC Number:
- 234-304-1
- EC Name:
- Isooctylphenol
- IUPAC Name:
- Isooctylphenol
- Details on test material:
- - Name of test material (as cited in study report): Isooctylphenol
- Analytical purity: 93,1 %
- Other: investigation was conducted with a 56.8 % premixture of Wessalon S (high dispersed silicate, roentgen amorph, Degussa, Hanau)
- Other: Stability of test substance in feed was analytically tested
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Züchter Winkelmann, Borchen
- Strain. BOR: WISW (SPF Cpb)
- Age at study initiation: 28 to 35 days
- Weight at study initiation: mean value 69g (male/female)
- Housing: Makronlon cages type II on dust free wood granulate
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +- 2°C
- Humidity (%): no data
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Isooctylphenol was mixed into the rat feed .
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): Altromin R-Pulverfutter (source: Altromin GmbH, Lage)
- Storage temperature of food: no data - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- stability of test substance in feed was verified analytically during the test period.
- Duration of treatment / exposure:
- 3 months
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 30, 300, 3000 ppm (0, 2.2, 22.5, 227.9 mg/kg/d in males)
Basis:
nominal in diet
- No. of animals per sex per dose:
- 20
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: no data
- Rationale for selecting satellite groups: random - Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: after 1 and 3 month
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- 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: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes (body weight gain shown in graphical form: bodyweight plotted against time for each dose group and sex)
WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: 1 and 3 months after begin of administration
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: 5 per sex per dose group
- Parameters checked stated in section "any other information on materials and methods" were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 1 and 3 months after begin of administration
- Animals fasted: Yes
- How many animals: 5 per sex per dose group
- Following parameters were examined: blood glucose, partial thromboplastin time.
URINALYSIS: Yes
- Time schedule for collection of urine: after 1 and 3 month; 16 hours
- Metabolism cages used for collection of urine: No
- Animals fasted: Yes
- Parameters checked stated in section "any other information on materials and methods" were examined.
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
Folgende Organe wurden gewogen: Schilddrüse, Thymus, Herz, Lunge, Leber, Milz, Nieren, Nebennieren, Hoden bzw. Ovarien, Gehirn.
HISTOPATHOLOGY: Yes
Nachstehende Organe wurden in Bouin'scher Flüssigkeit fixiert: Aorta, Augen, Darm (Duodenum, Jejunum, Ileum, Colon, Rectum, Caecum), Femur, Gehirn, Harnblase, Herz, Hoden Hypophyse, Leber, Lunge, Lymphknoten, Magen, Milz, Nebenhoden, Nebennieren, Nieren, Oesophagus, Speicheldrüsen, Ovarien, Pankreas, Prostata, Samenblase, Schilddrüse, Skelettmuskulatur, Thymus, Thrachea und Uterus sowie zusätzliche Leberproben (Lobus sinister) von je 5 Tieren/ Dosis/Geschlecht wurden für den Fettnachweis in Formol-Calcium fixiert.
Für die histopathologische Auswertung wurde das in Bouin'scher Flüssigkeit fixierte Material von männlichen und weiblichen Ratten der Kontroll- und der Dosisgruppe 3000 ppm Isooctylphenol in Paraplast eingebettet, geschnitten und mit HE gefärbt. Zusätzlich wurden die PAS-Reaktion für Nierenschnltte und die Oil-Red-0-Färbung für Leberschnitte (Formalinfixierung) angewandt. Die Entkalkung der Knochen erfolgte in einer EDTA-
Lösung. Das Material wurde in der Abteilung Histopathologie unter der Eingangsnummer 1559 registriert.
Zur histologischen Auswertung gelangten die nach oben genannten fixierten Organe von je 5 männlichen und 5 weiblichen Tieren der Kontroll-
gruppe und der höchsten Dosisgruppe mit Ausnahme des N.ischiadicus. Die Auswahl der Tiere erfolgte anhand einer Randomliste. - Other examinations:
- no data
- Statistics:
- Arithmetic means, standard deviation s, confidence intervals: 95% & 99%.
U-Test according MANN, WHITNEY and WILCOXON, level of significance: 5% & 1%.
Randomization according “Subprogram Randu" from the "Scientific Subroutine Package" (IBM-370).
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- effects observed, treatment-related
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
Während der Versuchszeit unterschieden sich die Ratten, die Isooctylphenol in Dosierungen von 30 bis 3000 ppm im Futter erhielten, im Aussehen und Verhalten nicht von den Kontrolltieren. Bei den Ratten der Dosierungen 30 bis 3000 ppm im Futter ergaben sich keine Unterschiede in der Lebhaftigkeit und Fellbeschaffenheit sowie im Fress- und Trinkbedürfnis.
Sterblichkeit: 1 Tier in Dosisgruppe 30 ppm und 1 Tier in Dosisgruppe 3000 ppm. Die Sterblichkeit war nicht behandlungsbedingt erhöht.
BODY WEIGHT AND WEIGHT GAIN
Die männlichen und weiblichen Ratten der Versuchsgruppe 30 ppm nahmen etwa wie die Kontrolltiere an Körpergewicht zu. Die Körpergewichtszunahme war nach 300 ppm vorwiegend bei Männchen leicht verzögert (~10%) (signifikant bei männlichen Tieren in der 3. und 10. Versuchswoche) während bei 3000 ppm die Gewichtszunahme gegenüber den Kontrolltieren deutlich verzögert war.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Die männlichen und weiblichen Ratten die den Wirkstoff bis zur Dosis 3000 ppm im Futter erhielten, nahmen in etwa so viel Pulverfutter auf wie die Kontrolltiere.
FOOD EFFICIENCY
In der 3000 ppm Gruppe waren die Körpergewichtszunahme und das Organwachstum behandelter Tiere deutlich verzögert.
WATER CONSUMPTION
Die Wasseraufnahme unterschied sich bei behandelten männlichen Tieren nicht bedeutsam von der der Kontrollgruppe. Die weiblichen Ratten der Dosierung 3000 ppm tranken ca. 28% mehr Wasser als die Kontrollweibchen.
OPHTHALMOSCOPIC EXAMINATION
nicht untersucht
HAEMATOLOGY
In der Gruppe bis 300 ppm ergaben sich keine Hinweise auf behandlungsbedingte Beeinflussung hämatologischer Parameter. Am Versuchsende waren Hämoglobingehalt sowie Hämatokritwert weiblicher Tiere der Dosisgruppe 3000 ppm signifikant gegenüber den Kontrollweibchen vermindert. Da dieser Befund nur zu einem Versuchszeitpunkt bei einem Geschlecht auftrat und die Werte innerhalb des altersgemäßen Normalbereichs weiblicher Tiere lagen, wird er als Zufallsbefund angesehen. Histopathologisch ergaben sich keine Hinweise auf eine behandlungsbedinqte Beeinflussung der Hämatopoese
CLINICAL CHEMISTRY
Die Thyroxinkonzentration bei weiblichen Tieren der Dosisgruppe 3000 ppm war gegenüber den Kontrollweibchen erhöht. Nach 3000 ppm wurde bei männlichen Tieren eine gegenüber den Kontrolltieren geringfügig erniedrigte Na-Konzentration gestellt. Diesem Befund wird jedoch, da der Wert innerhalb des altersgemäßen Streubereichs der Tiere lag, keine toxikologische Bedeutung beigemessen. In allen übrigen untersuchten Parametern unterschieden sich behandelte Ratten nicht bedeutsam und dosisabhängig von den Kontrollratten.
URINALYSIS
Die Befunde der Harnuntersuchungen nach 1 und 3 monatiger Versuchszeit bei jeweils 5 männlichen und 5 weiblichen Ratten/Dosisgruppe erbrachten keine auf die Behandlung zurückzuführenden Unterschiede zwischen Kontrolltieren und behandelten Ratten bis zur Versuchsgruppe von 3000 ppm.
NEUROBEHAVIOUR
nicht untersucht
ORGAN WEIGHTS
Dem zwar signifikant, aber nur geringfügig erniedrigten Schilddrüsengewicht männlicher Tiere wird, da es zudem nur bei einem Geschlecht erhoben wurde, keine toxikologische Bedeutung beigemessen. Die zum Teil signifikant erniedrigten Organgewichte behandelter Tiere ab 300 ppm sind als Folge der verzögerten Körpergewichtsentwicklung der Tiere anzusehen und wurden daher nicht als toxikologisch bedeutsam gewertet.
GROSS PATHOLOGY
Bei der Sektion der Überlebenden Tiere am Versuchsende wurden keine dosisabhängigen pathologischen Befunde erhoben.
HISTOPATHOLOGY: NON-NEOPLASTIC
In allen mikroskopisch untersuchten Organen sind keine dosisabhängig gehäuften Veränderungen aufgetreten.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 300 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: reduced body weight gain in week 3 and 10 only and small changes in organ weights
- Dose descriptor:
- LOAEL
- Effect level:
- 3 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: reduced body weight gain; changes in organ weights
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Compound consumption per dose group: |
|||
male |
|
|
|
|
30 ppm |
300 ppm |
3000 ppm |
g food/animal |
1533 |
1509 |
1470 |
mg compound/animal |
46,0 |
452,7 |
4410,0 |
mg compound/animal/day |
0,5 |
5,0 |
49,0 |
mean bw (g); week 1-13 |
233 |
224 |
215 |
mg compound/kg bw/day |
2,2 |
22,5 |
227,9 |
|
|
|
|
female |
|
|
|
|
30 ppm |
300 ppm |
3000 ppm |
g food/animal |
1112 |
1077 |
1007 |
mg compound/animal |
33,4 |
323,1 |
3021,0 |
mg compound/animal/day |
0,4 |
3,6 |
33,6 |
mean bw (g); week 1-13 |
149 |
144 |
135 |
mg compound/kg bw/day |
2,5 |
24,9 |
248,6 |
Applicant's summary and conclusion
- Conclusions:
- Feeding 300 ppm (22.5 mg/kg/d) 4-(1,1,3,3-tetramethylbutyl)phenol for 90 day causes no adverse effects in Wistar rats under conditions of this study.
- Executive summary:
In a subchronic toxicity study 4-(1,1,3,3-tetramethylbutyl)phenol (93.1%) was fed to 20 Wistar rats/sex/dose at dose levels of 0, 30, 300, 3000 ppm for three months.
No treatment related mortality or clinical signs of toxicity were reported. No significant reduction in food consumption was reported.
In the high dose group mean body weight gain was significantly reduced. Water uptake was increased in females of the 3000 ppm dose group. Haematological parameters in all treated male rats were unaffected. A decrease in haemoglobin and haematocrit was reported among females at the high dose level at the end of the testing period. This was observed only at one particular time and in one sex. The values were in the normal range for females of this age. Thus this effect is considered to be incidental. No histopathological indications of dose-related effects on haematopoiesis were observed.
The thyroxin (T4) content was increased in females in the highest dose group after one month, but decreased to control levels after 3 month. This effect can be traced back to considerably increased thyroxin concentrations in two female test animals and might be dose-related. Histopathologically the thyroids of randomly selected animals of this dose group were normal. Body weight gain was slightly reduced in male rats in the 300 ppm dose group. Some significant reduced organ weights indicate a minor impairment of growth. Pathological-anatomical and histopathological investigations as well as clinical and chemical effects and organ weight indicated no adverse effects on liver and kidney up to dosages of 3000 ppm.
The LOAEL is 3000 ppm, based on delayed body weight gain, and associated reduced organ weights. The NOAEL is 300 ppm.
This subchronic toxicity study in the Wistar rats is acceptable and satisfies the guideline requirement for a subchronic oral study (OECD 408) in rats.
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