Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 223-095-2 | CAS number: 3734-33-6
- 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:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Justification for type of information:
- Data is from peer-reviewed journal
Data source
Referenceopen allclose all
- Reference Type:
- publication
- Title:
- Final Report of the Safety Assessment of Alcohol Denat.,IncludingSDAlcohol3-A,SDAlcohol30,SDAlcohol39,SDAlcohol39-B,SDAlcohol 39-C,SDAlcohol 40,SDAlcohol 40-B,SDAlcohol 40-C,and the Denaturants,Quassin,Brucine Sulfate/Brucine,and Denatonium Benzoate1
- Author:
- Cosmetic Ingredient Review Expert Panel
- Year:
- 2 008
- Bibliographic source:
- International Journal of Toxicology, 27(Suppl. 1):1–43, 2008
- Reference Type:
- review article or handbook
- Title:
- Unnamed
- Year:
- 1 977
- Report date:
- 1977
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: as below
- Principles of method if other than guideline:
- Chronic toxicity study of denatonium benzoate in cynomolgus monkeys
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Denatonium benzoate
- EC Number:
- 223-095-2
- EC Name:
- Denatonium benzoate
- Cas Number:
- 3734-33-6
- Molecular formula:
- C21H29N2O.C7H5O2
- IUPAC Name:
- N-benzyl-2-[(2,6-dimethylphenyl)amino]-N,N-diethyl-2-oxoethanaminium benzoate hydrate
- Test material form:
- solid
- Details on test material:
- - Name of test material (as cited in study report): N-benzyl-2-[(2,6-dimethylphenyl)amino]-N,N-diethyl-2-oxoethanaminium benzoate hydrate
-Common name: Denatonium benzoate
- Molecular formula: C21H29N2O.C7H5O2
- Molecular weight: 446.58 g/mol
- Substance type: organic
- Physical state: Solid
Constituent 1
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): Denatonium benzoate
- Molecular formula (if other than submission substance): C28H34N2O3
- Molecular weight (if other than submission substance): 446.58 g/mol
- Substance type: Organic
- Physical state: Solid
Test animals
- Species:
- monkey
- Strain:
- Macaca fascicularis
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: No data available
- Age at study initiation: No data Available
- Weight at study initiation:
Males: 1.60 to 3.45 Kg
Females: 1.40 to 2.90 Kg
- Fasting period before study: No data available
- Housing: The monkeys were housed individually in hanging wire mesh “squeeze type” cages
- Diet (e.g. ad libitum): Purina Monkey Chow was fed twice daily and fresh apples were fed three times a week
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 3 months
ENVIRONMENTAL CONDITIONS
- Temperature (°C): Controlled environment
- Humidity (%):Controlled environment
- Air changes (per hr): Controlled environment
- Photoperiod (hrs dark / hrs light): Controlled environment
IN-LIFE DATES: From: To: No data Available
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Denatonium benzoate was dissolved in distilled water so that a volume of 2 ml/kg/day was administered at all dosage levels. Individual daily doses were based upon the body weights obtained twice a week or weekly.
DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Water was used as a vehicle.
- Concentration in vehicle: 0, 1.6, 8.0 and 16.0 mg/kg body weight /day
- Amount of vehicle (if gavage): 2 ml/kg/day
- Lot/batch no. (if required): : No data available
- Purity: : No data available - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 2 year
- Frequency of treatment:
- Daily
Doses / concentrations
- Remarks:
- 0, 1.6, 8 and 16 mg/kg/day
- No. of animals per sex per dose:
- Total: 66
0 mg/kg bw/day: 8 male, 9 female
1.6 mg/kg bw/day: 8 male, 8 female
8.0 mg/kg bw/day: 9 male, 8 female
0 mg/kg bw/day: 8 male, 8 female - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Eight male and 8 female monkeys were initiated at each dosage level and also as a control group. Two monkeys dying during the first 6 weeks of study were replaced.
- Positive control:
- not specified
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily
BODY WEIGHT: Yes
- Time schedule for examinations: Twice weekly for first 5 weeks and weekly thereafter
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Not applicable
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data
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 / No / No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations:
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Once for control animals and at 3, 6 and 12 months of study for test animals
- Dose groups that were examined: All 66 animals were examined.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Once for control animals and at 3, 6 and 12 months of study for test animals
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all dose group animals
- Parameters checked: Hematological studies included hemoglobin , hematocrit , total erythrocyte count , total and differential leucocyte counts,
clotting time and platelet count
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Once for control animals and at 3, 6 and 12 months of study for test animals
- Animals fasted: No data
- How many animals: all dose group animals
- Parameters checked: Biochemical studies included fasting glucose, urea nitrogen , serum glutamic pyruvic and oxalacetic transaminase activities, serum alkaline phosphatase, carbon dioxide, serum total protein, serum electrophoresis, albumin, bilirubin, serum sodium, potassium, chloride, calcium and prothrombin time.
URINALYSIS: Yes
- Time schedule for collection of urine: Once for control animals and at 3, 6 and 12 months of study for test animals
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked: Urinalysis included measurement of volume, pH and specific gravity; description of color and appearance; qualitative tests for albumin, glucose, ketones, bilirubin and occult blood; and microscopic examination of the sediment
NEUROBEHAVIOURAL EXAMINATION: No data - Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:
OTHER:
Heart function was examined by using electrocardiograms
- Time schedule to obtained electrocardiograms: Once in quarantine period and at 3, 6 and 12 months of study.
- How many animals: All 66 animals were examined.
- Parameters checked in table [No.?] were examined: Variations or abnormalities were examined.
Organs weight :
Spleen, liver, adrenals, kidney, ovaries, liver, lung, thyroid, brine and pituitary were examined. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
At 3 months of study, 2 male and 2 female monkeys from the control and 1.6 mg/kg/day group, 2 males and 1 female from the 8 mg/kg/day group and 2 males fro mthe 16 mg/kg/day group.
At 3 months of study , 2 male and 2 female monkeys from the control group, 2 males and 1 female from 1.6 mg/kg/day group and 1 male and 2 females from each of the 8 mg/kg/day and 16 mg/kg/day groups were sacrificed
At the end of 12 months of study, all remaining monkeys were sacrificed and necropsied.
At necropsy selected organs were weighed and representative tissues from each monkey were collected in buffered neutral 10% formalin.
HISTOPATHOLOGY: Yes
Hematoxylin and eosin stained paraffin sections of tissues were prepared and examined.
Oil red 0 stained frozen sections of livers, from selected monkeys sacrificed at 3 months and, from those that died, were prepared and examined.
Organs examined.
Brain (3 levels),spinal cord (thoracic), sciatic nerve, eye, pituitary, thyroid/parathyroid, adrenals, trachea, lung, heart, spleen, lymph node (mesenteric), bone marrow (rib, junction), esophagus, stomach, small intestine (3 levels), large intestine, pancreas, liver, kidneys, urinary bladder, testes, epididymus/ovaries, prostate/uterus, seminal vesicles, skeletal muscle, skin (mammary gland) and any other tissue with gross lesions were examined. - Other examinations:
- not specified
- Statistics:
- not specified
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- No effect was observed on treated monkeys as compared to control.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- When treated with 16 mg/kg bw/day, 2 male and 2 female died on 9th, 11th, 17th and 31st week of study.
When treated with 8 mg/kg bw/day 2 male and 1 female died on 3rd, 10th and 18th week of study.
When treated with 1.6 mg/kg bw/day, 1 female died on 21 weeks of study and one animal died in control group. - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Treated male monkeys gained less body weight as compared to control monkeys. Female monkeys, control and treated, generally maintained or showed slight gains in body weight.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Description (incidence and severity):
- No ophthalmoscopic changes were observed in treated monkeys as compared to control.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- When treated with 1.6 mg/kg bw/day, marked decreases in hemoglobin, hematocrit and total erythrocyte count for one female monkey were observed at 3 months of study. Changes were considered to be incidental.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No changes were observed in clinical chemistry of treated monkeys as compared to control.
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- No changes in urinalysis were observed in treated monkeys as compared to control.
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- No behaviour changes were observed in treated monkeys as compared to control.
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No absolute and relative changes in organ weight were observed in treated monkeys.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No compound related gross pathologic lesions were observed in any of the monkeys which were sacrificed at 3 months, 6 months, or 1 year, or which died during the course of study.
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No microscopic lesions were observed in tissues from monkeys sacrificed at 3 months from 8 or 16 mg/kg bw /day group or those sacrificed at 6 months or 1 year at the 16 mg/kg/day group or in monkeys which died during the course of the study.
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- no effects observed
- Description (incidence and severity):
- No effect on electrocardiograms were observed in treated monkeys.
Effect levels
- Dose descriptor:
- LOAEL
- Effect level:
- 8 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- mortality
- other: Effect on survival of monkeys
Target system / organ toxicity
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Treatment related:
- not specified
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
Applicant's summary and conclusion
- Conclusions:
- LOEAL was considered to be 8 mg/kg bw when Macaca fascicularis (cynomolgus) male and female monkeys were treated with denatonium benzoate orally by gavage for 2 years.
- Executive summary:
A Chronic toxicity study, Macaca fascicularis (cynomolgus) male and female monkeys were treated with denatonium benzoate n the concentration of 0, 1.6, 8 and16 mg/kg/day orally by gavage. 2 male and 2 female died on 9th, 11th, 17thand 31st week of study at 16 mg/kg bw/day, 2 male and 1 female died on 3rd, 10thand 18thweek of study at 8 mg/kg bw/day and 1 female died on 21 weeks of study and one animal died in control group at 1.6 mg/kg bw/day. No effect on clinical sign and behaviour changes were observed on treated monkeys as compared to control. Treated male monkeys gained less body weight as compared to control monkeys. Female monkeys, control and treated, generally maintained or showed slight gains in body weight. No ophthalmoscopic changes were observed in treated monkeys as compared to control. Marked decreases in hemoglobin, hematocrit and total erythrocyte count for one female monkey were observed at 3 months of study at 1.6 mg/kg bw/day. Changes were considered to be incidental. No changes were observed in clinical chemistry, urinalysis and electrocardiograms of treated monkeys as compared to control. No absolute and relative changes in organ weight and no compound related gross pathologic lesions were observed in any of the monkeys which were sacrificed at 3 months, 6 months, or 1 year, or which died during the course of study. No microscopic lesions were observed in tissues from monkeys sacrificed at 3 months from 8 or 16 mg/kg bw /day group or those sacrificed at 6 months or 1 year at the 16 mg/kg/day group or in monkeys which died during the course of the study. Therefore, LOEAL was considered to be 8 mg/kg bw when Macaca fascicularis (cynomolgus) male and female monkeys were treated with denatonium benzoate orally by gavage for 2 years.
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.