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EC number: 401-700-2 | CAS number: 3100-36-5 CYCLOHEXADECENON; CYCLOHEXADECENONE
- 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
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- Auto flammability
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- 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
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- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
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- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
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- Endpoint summary
- Stability
- Biodegradation
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- 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
In the key subacute feeding study in male and female Wistar rats according to OECD guideline 407, the NOAEL was 232.25 mg/kg bw/day in males and 250.75 mg/kg bw/day in females.
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1986-05-27 to to 1986-10-24
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- yes
- Remarks:
- compared to the current version, some endpoints were not examined
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- 1981-05-12
- Deviations:
- yes
- Remarks:
- compared to the current version, some endpoints were not examined
- Principles of method if other than guideline:
- Compared to the current version of OECD guideline 407, some endpoints were not examined (no analytical verification of test concentrations, no detailed clinical observations, no functional observations, not all organs according to OECD 407 examined).
- A few clinical chemistry determinations in the plasma were not carried out in a single male or female rat because the sample had clotted or because the sample was lost at bleeding.
- Urinary volume and density were not recorded in one female of the control group because unreliable values were obtained.
- The ovaries of one rat of the low-dose group were not weighed because of the presence of cystically dilated follicles. - GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- Bor: WISW (SPF;Cpb)
- Details on species / strain selection:
- The rat is the commonly used species for repeated-dose toxicity studies. The Wistar strain is a common laboratory strain with a good historical control data base.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 6-7 weeks
- Weight at study initiation: 146.1 - 146.4 g (males) and 121.4 - 121.7 g (females)
- Housing: 5 per sex per cage in suspended, stainless steel cages, fitted with wire-screen bottom and front (during acclimatation)
- Diet: Ad libitum (basal diet for rats and mice)
- Water: Ad libitum (tap water)
- Acclimation period: 13 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 + 2
- Humidity (%): At least 40
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From day 0 to day 28 - Route of administration:
- oral: feed
- Details on route of administration:
- The oral route is the likely route for human exposure.
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: The diet with the highest concentration was prepared first by adding the appropriate amount of the test substance (liquidized at 30°C) to the stock diet. The diets with the lower concentrations were obtained by diluting the top-dose diet with stock diet. Homogeneity of the diets was achieved by mixing for 2 minutes in a mechanical blender (Stephan cutter). Batches of 4 kg of each of the diets were prepared twice during the study. Immediately after preparation of the diets, samples were taken and subsequently stored at -20°C.
DIET PREPARATION
- Rate of preparation of diet: Twice during the study, on day 0 and day 14 of the study.
- Mixing appropriate amounts with powdered stock diet
- Storage temperature of food: The diets were stored at approx. 15°C until use. - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Continuously (feed)
- Dose / conc.:
- 1 190.5 mg/kg bw/day (actual dose received)
- Remarks:
- 15000 ppm in feed, corresponding to 1027-1341 mg/kg bw/day (females)
- Dose / conc.:
- 1 198.75 mg/kg bw/day (actual dose received)
- Remarks:
- 15000 ppm in feed, corresponding to 1004-1320 mg/kg bw/day (males)
- Dose / conc.:
- 250.75 mg/kg bw/day (actual dose received)
- Remarks:
- 3000 ppm in feed, corresponding to 219-274 mg/kg bw/day (females)
- Dose / conc.:
- 232.25 mg/kg bw/day (actual dose received)
- Remarks:
- 3000 ppm in feed, corresponding to 194-269 mg/kg bw/day (males)
- Dose / conc.:
- 49.5 mg/kg bw/day (actual dose received)
- Remarks:
- 600 ppm in feed, corresponding to 43-55 mg/kg bw/day (females)
- Dose / conc.:
- 45.75 mg/kg bw/day (actual dose received)
- Remarks:
- 600 ppm in feed, corresponding to 38-53 mg/kg bw/day (males)
- No. of animals per sex per dose:
- 5 animals per sex per dose
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: As the oral LD50 was >10000 mg/kg bw, the test substance was tested up to a limit dose of 1000 mg/kg bw/day. For mid and low doses, a 5-fold spacing was used.
- Fasting period before blood sampling for clinical biochemistry: Yes, for the 24-day collection (deprivation of water for 24 hours and of food during the last 16 hours of this period) - Positive control:
- Not included
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations included: General condition, behaviour, signs of ill health or reaction to treatment
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: Initially and on day 7, 14 ,21 and 28 of the study.
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No (Food intake was measured per cage (5 animals) weekly)
- 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: No (efficiency of food utilization was calculated and expressed as gram weight gain per gram food consumed)
WATER CONSUMPTION AND COMPOUND INTAKE: Yes (water intake was measured on a cage basis (5 animals))
- Time schedule for examinations: During the first week of the study
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: On day 22
- 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: Yes
- Time schedule for collection of blood: On day 24 (blood glucose) and on day 28
- Anaesthetic used for blood collection: Ether anaesthesia (terminal blood collection on day 28)
- Animals fasted: Yes, for the 24-day collection (deprivation of water for 24 hours and of food during the last 16 hours of this period)
- How many animals: All animals
- Parameters checked in table 2 were examined.
PLASMA/SERUM HORMONES/LIPIDS: No
URINALYSIS: Yes
- Time schedule for collection of urine: From day 24 to day 25
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Yes (Animals were deprived of water for 24 hours and of food for 16 hours. Urine was collected from individual animals during the last 16 hours of the deprivation period)
- Parameters examined: Volume and density of the urine
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 3)
HISTOPATHOLOGY: Yes (see table 4) - Statistics:
- Data an body weights were evaluated by one-way analysis of co-variance followed by Dunnett's multiple comparison test. Data on red blood cell variables, clinical chemistry values, volume and density of the urine, and organ weights were evaluated by one-way analysis of variance (ANWK) followed by Dunnett's multiple comparison test. Differential white blood cell counts were analyzed by the Mann-Whitney U-test. The histopathological changes were examined by Fisher's exact probability test.
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weights were significantly decreased in the top-dose group in both sexes (up to 23%, >10% during the whole study in males and up to 10% in females). Body weights were relatively low in males of the mid-dose group (non-significant, up to 7% lower than the control group)
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food intake was decreased in the top-dose group in both sexes (up to 22% in males and up to 11% in females), whereas females tended to recover at the end of the study.
Food intake was relatively low in males of the mid-dose group (up to 10% lower than the control group). - Food efficiency:
- effects observed, treatment-related
- Description (incidence and severity):
- Food conversion efficiency was decreased in the top-dose group in both sexes (up to 50% in males females) whereas females tended to recover at the end of the study.
Food conversion efficiency was relatively low in males of the mid-dose group (up to 21% lower compared to the control). - Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 15000 ppm: Red blood cell count and packed cell volume were increased in males, while haemoglobin concentration showed a tendency toward higher values. Packed cell volume was increased, MCHC was slightly decreased and red blood cell count and haemoglobin concentration showed a tendency toward higher values in females. These effects are considered to be a result of the lower body weight gain in this group.
3000 ppm: A decrease in thrombocytes count was observed in males which was considered incidential as no dose-dependence was observed.
600 ppm: A shift in the lymphocytes /neutrophils ratio was observed in females which was considered incidential. - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 15000 ppm: Plasma urea and creatinine concentrations were increased in males. GPT activity was increased and albumin concentration decreased in females.
600 ppm: A decrease in GOT activity was observed in males which was considered incidential as no dose-dependence was observed. - Endocrine findings:
- not examined
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The urinary volume was relatively low whereas the density was increased in the top-dose group in both sexes.
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- 15000 ppm: The absolute and relative weights of the liver were increased in both sexes (50% increase of the relative liver weight in males and 30% increase of the relative liver weight in females). The absolute and relative weights of the adrenals were decreased in females (28% decrease of relative adrenal weight compared to the control). Decreases observed in the absolute weights of the spieen, heart, ovaries and testes in the top-dose group are considered to be secondary to the reduction in body weight gain in this group.
3000 ppm: The absolute and relative weights of the liver were increased in males (21% increase of the relative liver weight) - Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- 15000 ppm: Moderate hepatocellular cytoplasmic alterations in both sexes (5/5 male animals and 4/5 female animals)
3000 ppm: Very slight hepatocellular cytoplasmic alterations in 1/5 males - Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 250.75 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- food consumption and compound intake
- food efficiency
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 232.25 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- food efficiency
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
- Key result
- Critical effects observed:
- no
- Conclusions:
- In a subacute feeding study according to OECD guideline 407, the NOAEL was 232.25 mg/kg bw/day in male and 250.75 mg/kg bw/day in female Wistar rats.
- Executive summary:
In a GLP compliant study according to OECD guideline 407, the toxicity of the test item was examined in four groups of 5 male and 5 female Wistar rats, which received the test substance in the diet at dose levels of 0 (control), 600, 3000 and 15000 ppm (corresponding to 45.75, 232.25 and 1198.75 mg/kg bw/day in males and 49.5, 250.75 and 1190.5 mg/kg bw/day in females) for a period of 4 weeks. General condition, behaviour and survival were not adversely affected by the administration of the test item. Growth, food intake and food conversion efficiency were decreased in the top-dose group in both sexes, and were relatively low in males of the mid-dose group. Red blood cell count and packed cell volume were increased in the top-dose group (more pronounced in males than in females). This effect was considered secondary to the lower food consumption and body weight gain. In the top-dose group, increases were observed in plasma urea and creatinine concentrations in males and in GPT activity in females, whereas albumin concentration was decreased in females.The urine concentration test showed an increased urinary density in the top-dose group in both sexes. As changes were not accompanied by changes in kidney weight or in microscopic renal morphology and the urine concentration test did not provide any indication of impaired kidney function, it was concluded that no nephrotoxic effect of the test substance was found. The weight of the liver was increased in males and females of the top-dose group and in males of the mid-dose group. The weight of the adrenals was decreased in females of the top-dose group. Gross examination at autopsy did not reveal any treatment-related changes. Upon microscopic examination, hepatocellular cytoplasmic alterations were observed in all males and all females of the top-dose group and in a single male of the mid-dose group.
Based on the results, the no observed adverse effect level (NOAEL) of the test item in the present study was found to be 232.25 mg/kg bw/day (3000 ppm) in males and 250.75 mg/kg bw/day (3000 ppm) in females.
Reference
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 232.25 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Reliable with restrictions (RL2)
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
Key, subacute feeding study, rat, RL2
In a GLP compliant study according to OECD guideline 407, the toxicity of the test item was examined in four groups of 5 male and 5 female Wistar rats, which received the test substance in the diet at dose levels of 0 (control), 600, 3000 and 15000 ppm (corresponding to 45.75, 232.25 and 1198.75 mg/kg bw/day in males and 49.5, 250.75 and 1190.5 mg/kg bw/day in females) for a period of 4 weeks. General condition, behaviour and survival were not adversely affected by the administration of the test item. Growth, food intake and food conversion efficiency were decreased in the top-dose group in both sexes, and were relatively low in males of the mid-dose group. Red blood cell count and packed cell volume were increased in the top-dose group (more pronounced in males than in females). This effect was considered secondary to the lower food consumption and body weight gain. In the top-dose group, increases were observed in plasma urea and creatinine concentrations in males and in GPT activity in females, whereas albumin concentration was decreased in females. The urine concentration test showed an increased urinary density in the top-dose group in both sexes. As changes were not accompanied by changes in kidney weight or in microscopic renal morphology and the urine concentration test did not provide any indication of impaired kidney function, it was concluded that no nephrotoxic effect of the test substance was found. The weight of the liver was increased in males and females of the top-dose group and in males of the mid-dose group. The weight of the adrenals was decreased in females of the top-dose group. Gross examination at autopsy did not reveal any treatment-related changes. Upon microscopic examination, hepatocellular cytoplasmic alterations were observed in all males and all females of the top-dose group and in a single male of the mid-dose group.
Based on the results, the no observed adverse effect level (NOAEL) of the test item in the present study was found to be 232.25 mg/kg bw/day (3000 ppm) in males and 250.75 mg/kg bw/day (3000 ppm) in females.
Justification for classification or non-classification
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on repeated dose toxicity, the test item is not classified and labelled for Specific target organ toxicity (repeated exposure) (STOT-RE) according to Regulation (EC) No 1272/2008 (CLP), as amended for the eighteenth time in Regulation (EU) 2022/692.
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