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EC number: 203-569-5 | CAS number: 108-29-2
- 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
Endpoint summary
Administrative data
Description of key information
Repeated dose toxicity, oral
The toxicity of the test item after repeated dose exposure was tested in three studies. The administration of the test item by gavage to female Wistar rats for 2 weeks caused no treatment-related, relevant effects at a dose of 1000 mg/kg bw. Thus, the NOAEL was found to be ≥1000 mg/kg bw in this study. A 90-Day feeding study in rats receiving dietary doses of the test item revealed no evidence of adverse toxic effects (NOAEL ≥ 49 (males) or 51.1 (females) mg/kg bw). A 13 week feeding study in rats showed no treatment-related effects at doses of 500 mg/kg bw. Thus the NOAEL was found to be ≥500 mg/kg bw.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- Not available, publication received 1966-11-07
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - Principle of test: The subacute and/or chronic toxicity of 48 food flavourings was studied in rats. A summary of the studies is presented.
- Short description of test conditions: 0, 1000, 2500, 5000 and 10000 ppm of the test item (corresponding to 0-500 mg/kg bw) were given to rats via. feed for 13 weeks.
- Parameters analysed / observed: Body weights were recorded weekly and hematological examinations were made at termination of the study. Organ weights of kidneys, spleen, heart, and testes were recorded. These organs, the remaining abdominal and thoracic viscera, and one hind leg, for bone, bone marrow and muscle, were preserved in 10 % buffered formalin-saline solution for histopathological examination. - GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Weanling Osborne-Mendel
- Details on species / strain selection:
- Not specified
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Housing: Individually in wire cages
- Diet: Ad libitum
- Water: Ad libitum - Route of administration:
- oral: feed
- Details on route of administration:
- Not specified
- Vehicle:
- not specified
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet: Fresh diets were made and distributed weekly - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- Not specified.
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Not specified.
- Dose / conc.:
- 10 000 ppm
- Remarks:
- equivalent to 500 mg/kg bw based on the conversion factors for old rats available in the JECFA guidelines for the preparation of toxicological working papers on Food Additives (JECFA, 2000)
- Dose / conc.:
- 5 000 ppm
- Remarks:
- equivalent to 250 mg/kg bw based on the conversion factors for old rats available in the JECFA guidelines for the preparation of toxicological working papers on Food Additives (JECFA, 2000)
- Dose / conc.:
- 2 500 ppm
- Remarks:
- equivalent to 125 mg/kg bw based on the conversion factors for old rats available in the JECFA guidelines for the preparation of toxicological working papers on Food Additives (JECFA, 2000)
- Dose / conc.:
- 1 000 ppm
- Remarks:
- equivalent to 50 mg/kg bw based on the conversion factors for old rats available in the JECFA guidelines for the preparation of toxicological working papers on Food Additives (JECFA, 2000)
- No. of animals per sex per dose:
- 10000 ppm: 11 males + 10 females
2500 ppm: 11 males + 9 females
5000 ppm: Not indicated
1000 ppm: 10 males + 10 females - Control animals:
- yes
- Details on study design:
- - Rationale for animal assignment: Litter mates were used except for a few subacute studies in which the weanlings were randomized by weight (every level having animals of equal weight).
- Positive control:
- Not specified
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Not specified
DETAILED CLINICAL OBSERVATIONS: Not specified
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption was determined weekly, calculation method is not specified
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: Not specified
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the termination of the experiments the rats were sacrificed and exsanguinated.
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: All animals
- Parameters checked in table 1 were examined.
CLINICAL CHEMISTRY: Not specified
PLASMA/SERUM HORMONES/LIPIDS: Not specified
URINALYSIS: Not specified
NEUROBEHAVIOURAL EXAMINATION: Not specified
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see "Any other information on material and methods incl. tables") - Optional endpoint(s):
- Optional endpoints: No
- Other examinations:
- No other examinations were indicated
- Statistics:
- Not specified.
- Clinical signs:
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- Not specified
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Not specified
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- Not specified
- Clinical biochemistry findings:
- not specified
- Endocrine findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Not specified
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- Not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 500 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Critical effects observed:
- no
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- Not available, publication received 1965-05-17
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - Principle of test: Subchronic feeding study, not all parameters of a guideline study were investigated.
- Short description of test conditions: Dosages were administered on a uniform body weight basis by weekly adjustments of the concentration of the test material in the cotton-seed oil.
- Parameters analysed / observed: Body weight, clinical chemistry, haematology, histopathology - GLP compliance:
- not specified
- Limit test:
- no
- Specific details on test material used for the study:
- The substance supplied were typical of the commercial grade and were not chemically pure in all instances.
- Species:
- rat
- Strain:
- other: FDRL strain
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Housing: Individually in wiremesh cages
- Diet: Ad libitum
- Water: Ad libitum - Route of administration:
- oral: feed
- Details on route of administration:
- Dosages were administered on a uniform body weight basis by weekly adjustments of the concentration of the test material in the cotton-seed oil. Food consumption records were maintained to compare the observed with the expected dosages of the test materials.
- Vehicle:
- cotton seed oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Each test substance was diluted in cotton-seed oil in a concentration sufficient to provide the predetermined dosage in 2% of the diet.
DIET PREPARATION
- Mixing appropriate amounts with: Purina Laboratory Chow
VEHICLE
- Justification for use and choice of vehicle: Cotton seed oil is a widely used vehicle for feeding studies
- Concentration in vehicle: In a concentration sufficient to provide the predetermined dosage in 2% of the diet - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- Not specified
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- Not indicated
- Dose / conc.:
- 51.1 mg/kg bw/day (actual dose received)
- Remarks:
- females
- Dose / conc.:
- 49 mg/kg bw/day (actual dose received)
- Remarks:
- males
- No. of animals per sex per dose:
- 15 animals per sex per dose
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: Dosage levels were derived from the human total estimated daily intake, calculated on a mg/kg body weight basis assuming 50 kg as the average body weight, and multiplying by 100. Thus a "no-effect" response at this dosage would indicate that the estimated maximum use level complied with the application of a 1 :100 safety factor.
- Positive control:
- Not indicated
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Not specified
DETAILED CLINICAL OBSERVATIONS: Not specified
BODY WEIGHT: Yes
- Time schedule for examinations: Not specified
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified
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: Not specified
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At a 6-week period (on 8 rats of each sex), at 12 weeks (in all rats)
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- Parameters examined: hematocrit (%), hemolglobin (g/100 mL), red blood cells (x 10^6/mm³), white blood cells (x 10^3/mm³), neutrophils (%), lymphocytes (%), blood urea nitrogen (mg/100 mL)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At a 6-week period (on 8 rats of each sex), at 12 weeks (in all rats)
- Animals fasted: Not specified
PLASMA/SERUM HORMONES/LIPIDS: Not specified
URINALYSIS: Not specified
NEUROBEHAVIOURAL EXAMINATION: Not specified
IMMUNOLOGY: Not specified - Sacrifice and pathology:
- GROSS PATHOLOGY: Not specified
HISTOPATHOLOGY: Yes (see table 1) - Optional endpoint(s):
- Optional endpoints: No
- Other examinations:
- No
- Statistics:
- Not specified
- Clinical signs:
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Both sexes responded with reduced leucocyte counts, despite normal differential counts, and in the case of the males, slightly lower red cell counts than the corresponding controls. The degree of difference was small when compared with the individual rather than the composite control group (6~99 versus 8~08 x 10^6/mm³). None of the deviations shown for the test group can be regarded as
pathological even though they fall somewhat outside the statistical limits (P=0~05) for the controls . - Clinical biochemistry findings:
- no effects observed
- Endocrine findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Various degrees of mild thyroid hyperplasia but this observation was also noted in the corresponding control groups and is not an uncommon finding in the laboratory. Despite these occasional aberrations, the opinion of the consultant pathologist who examined all slides resulting from this study was that none of the effects are be dose-related.
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 51.1 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 49 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Critical effects observed:
- no
- Endpoint:
- short-term repeated dose toxicity: oral
- Remarks:
- 14-day repeated-dose oral toxicity study
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 2019-09-24 to 2019-11-06
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Justification for type of information:
- A 14-day range-finding test with non-pregnant animals was conducted previous to an OECD 422 study with gamma-Valerolactone. The combined repeated dose toxicity study with the reprod./develop. tox. screening test, OECD 422, rats (gavage) is ongoing, the results will be submitted as soon as the data are available.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- Not all parameters indicated in the guideline were investigated and a shorter period of time (14 days) was chosen.
- Principles of method if other than guideline:
- - Principle of test: 14-day range-finding test study to obtain initial information on the effect of the test substance after repeated oral administration (gavage) to non-pregnant, female Wistar rats before the beginning of subsequent maternal and prenatal toxicity studies.
- Short description of test conditions: Not all parameters indicated in the guideline were investigated. - GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Batch number of test material: Zimmerma 00003
- Expiration date of the batch: 12 Aug 2021
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature - Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- The rat is the preferred animal species for repeated dose toxicity studies according to the various test guidelines. This Wistar rat strain (Crl:Wl(Han)) is selected because extensive historical control data is available for these rats.
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Females non-pregnant: Yes
- Age at study initiation: About 15 weeks
- Housing: Polysulfonate cages Typ 2000P (H-Temp) with dust-free wooden bedding. Cages were enriched with wooden gnawing blocks and large play tunnels.
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: 29 days
DETAILS OF FOOD AND WATER QUALITY:
The food used in the study was assayed for chemical and microbial contaminants. Fed. Reg. Vol. 44, No. 91 (09 May 1979), p 27354 (EPA), served as the guideline for maximum tolerable contaminants. Additionally, the levels of phytoestrogens should not exceed 350 μg of genistein equivalents/gram. According to recommendations of the GVSOLAS, the total amount of bacteria must not exceed 1*10^5 per g food.
The drinking water is regularly assayed for chemical contaminants both by the municipal authorities of Frankenthal and by the Environmental Analytics Water/Steam Monitoring Department of BASF SE as well as for bacteria by a contract laboratory. The Drinking Water Regulation will serve as the guideline for maximum tolerable contaminants.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 45-65
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From day 0 to day 14 - Route of administration:
- oral: gavage
- Details on route of administration:
- The oral administration of a test substance has been proven useful worldwide in numerous studies for discovering a potential toxicological profile.
- Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
For the test substance preparation, the specific amount of test substance is weighed, topped up with deionized water in a graduated flask and intensely mixed with a magnetic stirrer until it is completely dissolved. Before and during administration, the preparations is kept homogeneous with a magnetic stirrer.
VEHICLE
- Concentration in vehicle: 3 g/100 mL (for 300 mg/kg bw group) and 10 g/100 mL (for 1000 mg/kg bw group)
- Amount of vehicle: 10 mL/kg bw - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- From day 0 to day 14
- Frequency of treatment:
- Daily
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 3 animals per sex per dose
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: Low and high dose levels as requested by the sponsor
- Rationale for animal assignment: According to their weight - Positive control:
- No positive control included
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily (mondays-fridays) or once daily (saturdays, sundays and public holidays)
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Within 2 hours and between 2 and 5 hours after the administration, afterwards daily observations
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights are recorded on days 0, 3, 7, 10, and 13.
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
PLASMA/SERUM HORMONES/LIPIDS: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No - Sacrifice and pathology:
- One day after the last administration, the animals were anesthetized with isoflurane, sacrificed by decapitation and assessed by gross pathology.
- Optional endpoint(s):
- Optional endpoints: No
- Statistics:
- Body weight and body weight change: DUNNETT-test (two-sided)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Females of the 300 and 1000 mg/kg bw group, effects not further specified
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Endocrine 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:
- not examined
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Critical effects observed:
- no
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 500 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Comparable to guideline study with acceptale restrictions
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Repeated-dose toxicity (14 days), rat, RL2
A 14-day range-finding toxicity study has been conducted to obtain initial information on the effect of the test substance after repeated oral administration (gavage) to non-pregnant, female Wistar rats before the beginning of subsequent maternal and prenatal toxicity studies. Doses of 0, 300 and 1000 mg/kg bw in deionized water were given to three animals per dose. The test substance was administered to the animals orally by gavage for a maximum of 14 days. For this purpose, disposable syringes of suitable size and suitable gavage tubes were used. During the study, all animals were observed for any clinically abnormal signs. Furthermore, food and water consumption and body weights were recorded. One day after the last administration the animals were anesthetized with isoflurane, sacrificed by decapitation and assessed by gross pathology. The administration of the test item by gavage to female Wistar rats for 2 weeks caused no treatment-related, relevant effects. Thus, the NOAEL was found to be >1000 mg/kg bw (BASF 2019).
A Combined Repeated Dose Tox. Study with the Reprod./Develop. Tox. Screen. Test, OECD 422, rats (gavage) is ongoing, the results will be submitted as soon as the data are available.
Repeated-dose toxicity (90 days), rat, RL2
A 90-day repeated dose feeding study with the test item has been conducted in rats. Singe doses of 45.9 mg/kg bw in cotton seed oil were mixed with appropriate amounts of feed and given to 15 male and 15 female rats. The actual doses received were calculated as 49 mg/kg bw (males) and 51.1 mg/kg bw (females). Body weights, feed consumption, hematology, clinical chemistry and organ weights were evaluated. Based on the absence of treatment-related effects, the NOAEL was found to be >49 mg/kg bw (Oser et al., 1965).
Repeated-dose toxicity (13 weeks), rat, RL2
In the course of a screening of 48 food flavourings for repeated dose effects, 1000, 2500, 5000 and 10000 ppm of the test item (corresponding to 50-500 mg/kg bw) were given to rats via. feed for 13 weeks. Body weights were recorded weekly and hematological examinations were made at termination of the study. Organ weights of kidneys, spleen, heart, and testes were recorded. These organs, the remaining abdominal and thoracic viscera, and one hind leg, for bone, bone marrow and muscle, were preserved in 10 % buffered formalin-saline solution for histopathological examination. For routine histopathology, sections were embedded in paraffin wax and stained with haematoxylin and eosin. Tissues from rats dying during the experiment were examined for gross changes and were preserved if autolysis was not advanced. Organs were not weighed but abnormalities and the suspected reason for death were noted. No effects were found after treatment with the test item, thus the NOAEL was found to be >500 mg/kg bw (Hagan et al., 1966).
Repeated-dose toxicity, rat, RL4
Several possible metabolites of inethyl-n-butyl ketone were administered separately to rats in drinking water (0.25 - 1.0%, equals to 250-1000 mg/kg bw, as per the conversion factors for rat mentioned in the SOP) or by gavage (0.2-1.2 mg/kg). No effects were found, thus the NOAEL was found to be >1000 mg/kg bw. No further details were given (Opdyke 1962-1980, original study by Krasavage, O'Donoghue & Terhaar, 1978)
Justification for classification or non-classification
Classification, Labeling, and Packaging Regulation (EC) No 1272/2008
Using a weight of evidence approach, the repeated dose toxicity of the test item was assessed. The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. The test substance showed no toxicity after repeated exposure to rats, thus it is not considered to be classified for repeated dose toxicity under Regulation (EC) No 1272/2008, as amended for fifteenth time in Regulation (EU) No 2020/217.
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