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EC number: 203-157-5 | CAS number: 103-90-2
- 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:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other:
Data source
Referenceopen allclose all
- Reference Type:
- other: report
- Title:
- Toxicology And Carcinogenesis Studies Of Acetaminophen In F344/N Rats And B6c3f1 Mice (Feed Studies)
- Author:
- NTP Database
- Year:
- 1 993
- Bibliographic source:
- National Toxicology Program Technical Report Series No. 394
- Reference Type:
- review article or handbook
- Title:
- RTECS Number : AE4200000
- Author:
- RTECS database
- Year:
- 2 012
- Bibliographic source:
- RTECS (Registry of Toxic Effects of Chemical Substances):National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific & Technical Information. Volume(issue)/page/year: #PB85204667/AS
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other:
- Principles of method if other than guideline:
- Toxicology Study Of Acetaminophen In F344/N Rats (Feed Studies)
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Paracetamol
- EC Number:
- 203-157-5
- EC Name:
- Paracetamol
- Cas Number:
- 103-90-2
- Molecular formula:
- C8H9NO2
- IUPAC Name:
- .
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
- Details on test material:
- - Name of test material (as cited in study report): Paracetamol
- Substance type: Organic
- Physical state: Solid
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material:Acetaminophen was obtained from S.B. Penick & Company in two lots.Lot number 7042-LAR-5 was used.
- Purity :greater than 99%
RADIOLABELLING INFORMATION (Not applicable)
- Radiochemical purity: N/A
- Specific activity:N/A
- Locations of the label:N/A
- Expiration date of radiochemical substance:N/A
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:Throughout the studies, the bulk chemical was stored in sealed containers protected from light at 25 degC.
- Stability under test conditions:Stability studies performed with HPLC found that acetaminophen was stable as a bulk chemical when stored protected from light for 2 weeks at tempera- tures up to 60degC. Stability of the bulk chemical was monitored by the study laboratory using infrared and ultraviolet spectroscopies. No changein the study material was detected.
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories (Kingston, NY)
- Age at study initiation:Rats: 7-8 weeks old
- Housing:The rats were housed five per cage
- Diet (e.g. ad libitum):NIH-07 Rat and Mouse Ration, powdere (Zeigler Bros., Inc., Gardners, PA); available ad libitum
- Water (e.g. ad libitum):Tap water (City of Worcester Public Water Supply) via outside-the-cage automatic watering system (Edstrom Industries, Waterford, WI) available ad libitum
- Acclimation period: 19days
- Method ofAnimal Distribution: Animals distributed to weight classes and then assigned to test and control groupsso that all cage weights were equal for each sexand species.
- Animals per Cage: 5
- Method of Animal Identification: Ear punch
Bedding: AspenBed heat-treated hardwood chips (American ExcelsiorCo., Baltimore, MD); changed twice weekly
Cage Filters: Nonwoven fiber filters (Snow Filtration, Cincinnati, OH)
ENVIRONMENTAL CONDITIONS
- Temperature (°C):21.6°-27.2° C
- Humidity (%):34%-73%
- Air changes (per hr): 12-15/hour
- Photoperiod (hrs dark / hrs light):12hours/day
IN-LIFE DATES: From:23 February 1981 To:8 March 1981
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- other: diet
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency):once
- Mixing appropriate amounts with (Type of food):The dose formulations were prepared by mixing appropriate quantities of acetaminophen with feed in a blender. Dose formulations were prepared once for the 14-day studies.
- Storage temperature of food: 25 degC. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Studies were conducted by the analytical chemistry laboratory to determine homogeneity and stability of the dosed feed preparations. For homogeneity analyses, the formulations were extracted with methanol and the concentrations determined by an ultraviolet method at 247 nm. For the stability studies, the formulations were extracted using a methanol/acetic acid (95/5) solution and then injected into a HPLC system equipped with a µBondapak C18 column and a 254 nm detector. The mobile phase was methanol:water (24:76) with a flow rate of 1mL/minute.
Acetaminophen at the 20,000 ppm dose level mixed in rodent feed (NIH-07 Rat and Mouse Ration) produced a homogeneous blend and was found to be stable when stored protected from light in sealed containers at temperatures up to 25 degC. There was a 4% loss of chemical in feed stored 2 weeks at 45 degC.
Periodic analyses of the dose formulations of acetaminophen were conducted at the study laboratory and at the analytical chemistry laboratory using ultraviolet spectroscopy. For the 14day studies, dose formulations were analyzed prior to study initiation. - Duration of treatment / exposure:
- 14 Days
- Frequency of treatment:
- Daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 ppm
- Remarks:
- 0 mg/kgbw/day
- Dose / conc.:
- 800 ppm
- Remarks:
- 80 mg/kgbw/day
- Dose / conc.:
- 1 600 ppm
- Remarks:
- 160 mg/kgbw/day
- Dose / conc.:
- 3 100 ppm
- Remarks:
- 310 mg/kgbw/day
- Dose / conc.:
- 6 200 ppm
- Remarks:
- 620 mg/kgbw/day
- Dose / conc.:
- 12 500 ppm
- Remarks:
- 1250 mg/kgbw/day
- No. of animals per sex per dose:
- Control: 5 males and 5 females
80mg/kg: 5 males and 5 females
160mg/kg: 5 males and 5 females
310mg/kg: 5 males and 5 females
620mg/kg: 5 males and 5 females
1250mg/kg: 5 males and 5 females - Control animals:
- yes, plain diet
Examinations
- Observations and examinations performed and frequency:
- DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:clinical findings noted during the daily checks were recorded.
BODY WEIGHT: Yes
- Time schedule for examinations:The animals were weighed at study initiation and on days 7 and 14.
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: Feed consumption was measured weekly.
FOOD EFFICIENCY:No data
- 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: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:
OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
HAEMATOLOGY: No data
CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood:
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.
URINALYSIS: No data
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.
NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other: - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
Necropsy were performed on all animals.
HISTOPATHOLOGY: No - Statistics:
- Survival Analyses:
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958) and is presented in the form of graphS. Animals were censored from the survival analyses at the time they were found dead from other than natural causes. Animals dying from natural causes were not censored.Statistical analysis for a possible dose-related effect on survival used the method of Cox (1972) for testing two groups for equality and Tarone's (1975) life table
test to identify dose-related trends. All reported P values for the survival analysis are two sided.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Description (incidence):
- All rats survived to the end of the studies.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The final mean body weight of male rats receiving 1250 mg/kg bw/day acetaminophen was 20% lower than the mean final body weight of controls.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- The average feed consumption by male and female rats receiving 1250 mg/kg bw/day was lower than that of controls.
- Food efficiency:
- not examined
- 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:
- not examined
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- No compound-related lesions were found at necropsy and no histopathology was performed.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Effect levels
- Dose descriptor:
- LOEL
- Effect level:
- 12 500 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: effects on food consumption,body weight
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
|
** Significantly different (PSO.01) from the control group by Dunn's or Shirley's test
a Number suMng/number initially in group
Applicant's summary and conclusion
- Conclusions:
- The Lowest Observed Effect Level (LOEL) of Acetaminophen (Paracetamol) on rats by the oral route was observed at a dose concentration of 12500 ppm (1250 mg/kg bw) in a 14 days study period.
- Executive summary:
- The toxic effects of acetaminophen (paracetamol) were examined in a 14-day feed study in F344rats. Rats were fed diets containing 0, 800, 1,600, 3,100, 6,200, or 12,500 ppm acetaminophen.Different parameters like clinical effects,mortality,body weights,feed consumption and gross pathology were analyezed. All rats survived to the end of the studies . The final mean body weight of male rats receiving 1250 mg/kg acetaminophen was 20% lower than the mean final body weight of controls. The average feed consumption by male and female rats receiving 1250 mg/kg was lower than that of controls. No compound-related lesions were found at necropsy and no histopathology was performed.Thus from above findings we can conclude that the Lowest Observed Effect Level (LOEL) of Acetaminophen (Paracetamol) on rats by the oral route was observed at a dose concentration of 12500 ppm (1250 mg/kg bw) in a 14 days study period.
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