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EC number: 402-470-6 | CAS number: 87172-89-2 CINEOLE ALCOHOL
- 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:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1987-10-19 to 1987-11-20
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 988
- Report date:
- 1988
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- (1S,2S)-1-methyl-4-(propan-2-yl)-7-oxabicyclo[2.2.1]heptan-2-ol
- Cas Number:
- 87172-89-2
- IUPAC Name:
- (1S,2S)-1-methyl-4-(propan-2-yl)-7-oxabicyclo[2.2.1]heptan-2-ol
- Test material form:
- solid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Rats were supplied by Charles River U.K. Ltd., Manston, Kent. Approximately 60 weanling rats of each sex were delivered under Specific Pathogen Free (SPE) conditions in wire lined filter boxed to the SPF Experimental Unit, Sittingbourne Research Centre.
- Age at study initiation: 6 to 8 weeks
- Weight at study initiation: males: 153.5 - 162.0 g; females: 116.2 - 119.2 g
- Housing: The animals were singly housed
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: Approximately one week
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23 °C
- Humidity (%): 45-70%
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- The animals were dosed by oral intubation at 3 mL per kilogram body weight (based on the most recent body weight measurement) once each day until scheduled necropsy.
- Vehicle:
- other: polyethylene glycol:water (1:1 v/v)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test substance was formulated in polyethylene glycol: water (1:1 v/v). Solutions were prepared to provide the equivalent of 333 mg/mL, 166.6 mg/mL, 33.3 mg/mL, 3.33 mg/mL, 0.33 mg/mL and 0 mg/mL. The formulations were prepared weekly throughout the study and stored at approximately 30 °C to keep the test substance in solution.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Sub-samples of the test solutions were taken by volume and added to ethanol. The total volume was adjusted to a known value, and further dilutions, if required, were made using more ethanol. The solutions thus produced were analysed without further treatment using gas chromatography.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- once each day
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 10 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- Test group: 7/ sex
Control group: 14/sey - Control animals:
- yes, concurrent vehicle
Examinations
- Observations and examinations performed and frequency:
- DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice daily on weekdays and once daily on weekends
- Each animals was examined carefully for evidence of changes in skin, fur, eyes and visible mucous membranes, for abdominal patterns of behaviour, disturbance of major body systems (e.g. respiratory, alimentary, urinary, nervous system) and for goss deviations in food and water consumption.
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly intervals
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food hoppers were weighted at weekly filling and topped up later in the week; weekly food intakes during the study wer calculated.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood samples were taken from each animal at necropsy by cardiac puncture into tubes containing EDTA (ethylenediamine tetra-acetic acid)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At necropsy by cardiac puncture into tubes containing heparin.
- Animals fasted: No
- How many animals: All animals
For details refer to section 'Any other information on materials and methods incl. tables' - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see table) / No / Not specified - Statistics:
- A one-way analysis of variance with treatment and block factors was used for all variates. Following analysis of variance, differences between the control and treated group means were assessed for significance using the Williams' t test (Williams, 1971; Williams 1975). On occasions where a monotonic dose response could not be assumed, Dunnett's test was used (Dunnett, 1964).
Body and organ weights are reported as analysed with initial body weight as a covariate provided a significant covariance relationship was observed.
Organ weights were further analysed using terminal body weight as a covariate. Although not a true covariance analysis, the analysis does provide an aid to the interpretation of organ weights when there are differences in terminal body weights. The analysis attempts to estimate what the organ weights would have been if all the animals had had the same terminal body weight.
Wilcoxon's two sample rank sum test (Hill and Peto, 1971; Lehman, 1961) was used for BANDS (non-segmented polymorphic neutrophils) and IGT. Food intakes, and other clinical chemistry and haematology variates were examined using the analysis of variance.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- effects observed, treatment-related
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Liver weights were increased at 500 and 1000 mg/kg in males and at 500 and 1000 mg/kg in females, with histological evidence of enzyme induction and a macrovesicular vacuolation at 1000 mg/kg in both sexes.
Kidney weights were increased at 500 and 1000 mg/kg in males and at 1000 mg/kg in females. - Gross pathological findings:
- effects observed, treatment-related
- Neuropathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL OBSERVATIONS AND MORTALITY:
All top dose animals were comatose within a few hours of their first dose, except one male which became ataxic and then died and two males which were ataxic for about 5 hours. The coma lasted several hours, most animals recovered overnight but some died in coma or were humanely killed the next day; two others died or were killed after being comatose subsequent to their second dose. Few toxic signs were observed among the surviving animals, although coma did occur sporadically after approximately one dose in 13. One female died after being comatose in the last week of dosing.
Several of the animals with ataxia repeatedly scrached their heads.
Three animals appeared to have blood in their urine, two of these subsequently died.
At 500 mg/kg one male and four females had ataxia or abasia on the first day of dosing only, one other female had ataxia and abasia on the third day of dosing only; they had no other signs of toxicity.
Animals in the other dose groups survived to the end of the study with no significant clinical signs.
BODY WEIGHT AND FOOD INTAKE
The top dose animals had reduced food intakes and only gained about half as much body weight as the controls. The 500 mg/kg animals and the 100 mg/kg females had reduced body weights and food intakes throughout the study, although this was not always statistically significant.
ORGAN WEIGHTS
Liver weights were increased at 100, 500 and 1000 mg/kg in males, and at 500 and 1000 mg/kg in females. These increases may be related to a functional hypertrophy caused by exposure to xenobiotics resulting in a stimulation of the normal detoxification system.
Kidney weights were increased in both sexes at 1000 mg/kg, and at 500 mg/kg in males. this may be related to the blood seen in the urine of the top dose animals and the histopathological finfings.
Adrenal weights were increased in all top dose animals. The top doses males showed a small statistically significant increase in heart weight, of no toxicological importance.
PATHOLOGY
Treatment related macroscopic and microscopic observations were only found in the top dose group.
The livers of the top dose group had a range of minor tinctorial changes visible macroscopically that were inconsistent and of uncertain significance. Several animals had histological changes consistent with enzym induction, and a macrovesicular vacuolation which is considered related to treatment. the bladders of premature decedents had a range of lesions from mild submucosal haemorrhage to severe haemorrhagic cystitis. This typ of lesion is normally due to the presence of an irritant material in the bladder, i.e. the test substance or metabolite in the urine. No other treatment related histopathological changes were identified.
HAEMATOLOGY AND CLINICAL CHEMISTRY
Female rats at 500 and 1000 mg/kg had mild macrocytic hypochromic anaemia i.e. reduced haemoglobin and mean corpuscular haemoglobin concentration, and an increased erythrocyte volume. Females at 500 mg/kg also had a reduced erythrocyte count. At 100 mg/kg females gat a very mild normochromic anaemia i.e. reduced haemoglobin.
Male rats had no significant signs of anaemia as such, but both males and females had evidence of compensation for anaemia. Females at 10 to 100 mg/kg and males at 100 to 1000 mg/kg had increased reticulocytes and all animals at 100 mg/kg had increased normoblasts (females hat a non statistically significant increase).
Males had increased platelet counts at 100 to 1000 mg/kg and increased plateletcrit at 500 and 1000 mg/kg; females had an increased platelet count at 1000 mg/kg only. Mean platelet volumes were decreased at 500 and 1000 mg/kg in males and 100 to 1000 mg/kg in females. Females at 500 and 1000 mg/kg had increased polymorphic neutrophils and decreased in lymphocytes at 1000 mg/kg. This may reflect a mild inflammatory reaction. other small statistically sifnificant haematological changes are of no toxicological importance.
The haematological findings in the higher dose level my be related to the haemorrhagic effects seen in the bladders of the decedents i.e. the anaemia and increased platelets could be due to haemorrhage earlier in the study.
Although no macroscopic changes were observed at necropsy in the bladders of the survivors, it is likely that some haemorrhage did occur early in the study in some survivors e.g. blood was seen in the urine of one of the males in the top dose group on day 1.
All top dose animals had increased serum bilirubin, probably related to the increase in erythrocyte turnover.
Urea nitrogen and creatinine were increased at 500 mg/kg in males and decreased at 1000 mg/kg in females. There were no treatment related histopathological changes in the kidney, but kidney weights were increased in these groups as well as in the 1000 mg/kg males.
Cholesterol levels were increased in the 100 and 500 mg/kg males and triglycerides were decreased in females at 100 to 1000 mg/kg.
Alkaline phosphate levels were markedly decreased at 500 and 1000 mg/kg in both sexes. A decrease of this magnitude was probably due to a reduction in the intestinal alkaline phosphatase isoenzyme, brought about by either the reduced food intakes, or a direct effect of the compound on the intestine.
Other statistically significant clinical chemical differences are not toxicologically important.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
- haematology
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- System:
- haematopoietic
- Organ:
- other: hematopoietic system
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Applicant's summary and conclusion
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