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EC number: 248-096-5 | CAS number: 26896-48-0
- 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:
- 01 Feb 2013- 25 Oct 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study conducted to OECD guidelines and in compiance with GLP
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- Food consumption was recoreded for pre-treatment week. Method of analysis changed from HPLC to LC-MS/MS and LOD/LOQ not assessed. Any response form blank samples must be <20% lowest calibration standard.
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Certificate of compliance issued by UK MHRA included in report
- Limit test:
- no
Test material
- Reference substance name:
- TCD Alcohol DM
- IUPAC Name:
- TCD Alcohol DM
- Reference substance name:
- Tricyclodecanedimethanol
- EC Number:
- 248-096-5
- EC Name:
- Tricyclodecanedimethanol
- Cas Number:
- 26896-48-0
- Molecular formula:
- C12H20O2
- IUPAC Name:
- [3-(hydroxymethyl)tricyclo[5.2.1.0²,⁶]decan-8-yl]methanol
- Test material form:
- liquid: viscous
- Details on test material:
- - Name of test material (as cited in study report): TCD alcohol DM
- Substance type: Organic
- Physical state: clear, colourless very viscous liquid
- Analytical purity: 98%
- Lot/batch No.: 50000051564
- Expiration date of the lot/batch: 15 January 2014
- Storage condition of test material: Refrigerated in the dark
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: UK
- Age at study initiation: 41-47 days
- Weight at study initiation: Males = 133-173g: Females = 118-150g
- Housing: Cage: Polycarbonate body with a stainless steel mesh lid, changed at
appropriate intervals. Bedding: Wood based bedding which was changed at appropriate
intervals each week.
- Diet (e.g. ad libitum): Rat and Mouse No. 1 Maintenance Diet.
- Water (e.g. ad libitum): Potable water from the public supply. Non-restricted via polycarbonate bottles with sipper tubes.
- Acclimation period:12 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23 °C
- Humidity (%):40-70 %
-Air supply: Filtered fresh air which was passed to atmosphere and not recirculated.
- Photoperiod (hrs dark / hrs light): 12 h dark/12 hlight
IN-LIFE DATES: From: 07 May 2013 To: 28 Oct 2013
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- propylene glycol
- Remarks:
- + ethyl acetate (w.w)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Concentration in vehicle:0, 50, 100, 200 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Homogeneity and stability assessed before commencement of treatment and test material found to be stable for >24h at 2-8 deg C and for 15 days at ambient temperature.
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Daily
- No. of animals per sex per dose:
- 10 males and 10 females per treatment group
- Control animals:
- yes, concurrent vehicle
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
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: Yes
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: per-treatment and week 11
HAEMATOLOGY: Yes
- Time schedule for collection of blood: week 13
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: all
- Parameters checked: according to OECD 408
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 13
- Animals fasted: Yes
- How many animals: all
- Parameters checked: according to OECD 408
NEUROBEHAVIOURAL EXAMINATION: Yes
- Sensory reactivity and grip strength
- Touch response
- Huntingdon Life Sciences: PJJ0003
- Auditory startle reflex
- Tail pinch response
- Grip strength
- Motor activity
OTHER:
Sperm analysis: Immediately after scheduled sacrifice of each male, the left vas deferens, epididymis and testis was removed and the epididymis and testis were weighed.
-Analysis of: sperm motility, sperm morphology, sperm count
Oestrous cycles - vaginal smears - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Statistics:
- All statistical analyses were carried out separately for males and females.
The following data types were analysed at each timepoint separately:
Body weight, using gains over appropriate study periods
Grip strength and motor activity
Haematology and blood chemistry
Oestrous cycles
Organ weights, absolute and adjusted for terminal body weight
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- There were three deaths during treatment. Female Nos. 132, 136 and 140 receiving 1000 mg/kg/day were despatched for welfare reasons on Day 12, 80 and 13 of treatment respectively. Clinical signs prior to despatch included; Female No. 132: decreased activity, laboured/shallow/slow breathing, râles (wet), sneezing and dark eyes. Female No. 136: excessive chewing, irregular/laboured breathing, râles (wet), piloerection, and prominent eyes. Female No. 140: decreased activity, laboured/shallow breathing, râles (wet), piloerection, elevated gait and distended abdominal area. Macroscopic examination revealed abnormal contents (gas) and/or distension of the caecum, colon, ileum, jejunum, stomach and/or incomplete lung collapse in each of these animals with no direct histopathologic correlate. In addition, histopathological examination revealed: No. 132, minimal haemorrhage that correlated to dark, multilobular, diffuse areas of the lungs and minimal apoptosis of the thymus correlating to dark thymus areas; No. 136, small spleen within no microscopic correlate, minimal lung and bronchi perivascular cell infiltrate and inflammation, minimal apoptosis of the thymus correlating to dark thymus areas; No. 140, minimal apoptosis and decreased cellularity of the thymus with no macroscopic correlate and a small spleen with slight white pulp atrophy observed microscopically.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- There were three deaths during treatment. Female Nos. 132, 136 and 140 receiving 1000 mg/kg/day were despatched for welfare reasons on Day 12, 80 and 13 of treatment respectively. Clinical signs prior to despatch included; Female No. 132: decreased activity, laboured/shallow/slow breathing, râles (wet), sneezing and dark eyes. Female No. 136: excessive chewing, irregular/laboured breathing, râles (wet), piloerection, and prominent eyes. Female No. 140: decreased activity, laboured/shallow breathing, râles (wet), piloerection, elevated gait and distended abdominal area. Macroscopic examination revealed abnormal contents (gas) and/or distension of the caecum, colon, ileum, jejunum, stomach and/or incomplete lung collapse in each of these animals with no direct histopathologic correlate. In addition, histopathological examination revealed: No. 132, minimal haemorrhage that correlated to dark, multilobular, diffuse areas of the lungs and minimal apoptosis of the thymus correlating to dark thymus areas; No. 136, small spleen within no microscopic correlate, minimal lung and bronchi perivascular cell infiltrate and inflammation, minimal apoptosis of the thymus correlating to dark thymus areas; No. 140, minimal apoptosis and decreased cellularity of the thymus with no macroscopic correlate and a small spleen with slight white pulp atrophy observed microscopically.
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Week 13 : when compared with the controls, a statistically significant reduction in activated partial thromboplastin time in males which was dose-related and females receiving 500 or 1000 mg/kg/day (not statistically significant)
- Clinical biochemistry findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- high absolute and body weight-adjusted liver weights in males and females at 500 or 1000 mg/kg/day; high body weight-adjusted kidney weight in males with a dose-relationship and females given 1000 mg/kg/day apparent
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Changes seen in nasal turbinates related to teatment
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Changes related to treatment with TCD Alcohol DM were seen in the nose/turbinates.
- Details on results:
- Findings comprised of inflammatory exudate in the lumen of the nasal cavity and nasopharynx, degeneration/regeneration/inflammatory cell infiltration of the epithelium and deformity/fusion of turbinates. They were considered treatment related in all groups of both sexes.
Minimal findings, although not including turbinate changes, were seen in a single control female.
Changes of an uncertain relationship to treatment with TCD Alcohol DM were seen in the stomach.
Stomach - Epithelial hyperplasia of the non-glandular stomach was seen in occasional animals of both sexes given 500 and 1000 mg/kg/day and a single male given 250 mg/kg/day. In addition, a single case of erosion was seen in the non-glandular region of the stomach of a female given
1000 mg/kg/day. The low numbers affected and lack of consistency between the two sexes made this finding have an uncertain relationship to treatment.
All other microscopic findings were considered to be incidental and unrelated to treatment with TCD Alcohol DM.
No effects on sperm motility, morphology or concentration were observed after treatment at doses up to 1000 mg/kg/day.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: highest dose tested
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
There were three deaths during treatment. Female Nos. 132, 136 and 140 receiving 1000 mg/kg/day were despatched for welfare reasons on Day 12, 80 and 13 of treatment respectively.
Clinical signs prior to despatch included;
Female No. 132: decreased activity, laboured/shallow/slow breathing, râles (wet), sneezing and dark eyes.
Female No. 136: excessive chewing, irregular/laboured breathing, râles (wet), piloerection, and prominent eyes.
Female No. 140: decreased activity, laboured/shallow breathing, râles (wet), piloerection, elevated gait and distended abdominal area.
Macroscopic examination revealed abnormal contents (gas) and/or distension of the caecum, colon, ileum, jejunum, stomach and/or incomplete lung collapse in each of these animals with no direct histopathologic correlate.
In addition, histopathological examination revealed:
No. 132, minimal haemorrhage that correlated to dark, multilobular, diffuse areas of the lungs and minimal apoptosis of the thymus correlating to dark thymus areas;
No. 136, small spleen within no microscopic correlate, minimal lung and bronchi perivascular cell infiltrate and inflammation, minimal apoptosis of the thymus correlating to dark thymus areas;
No. 140, minimal apoptosis and decreased cellularity of the thymus with no macroscopic correlate and a small spleen with slight white pulp atrophy observed microscopically.
Microscopic findings were seen in the nose and comprised of inflammatory exudate in the lumen of the nasal cavity and nasopharynx, degeneration/regeneration/inflammatory cell infiltration of the epithelium and, deformity/fusion of turbinates. The microscopic changes in the nose/turbinates in two of the decedents (No. 132, 140) were of a severity to conclude that they were the factor responsible for the death whereas in the remaining animal (No. 136) these findings were not of a severity to be certain as to the cause of death. Similar findings in the nose/turbinates were also seen in terminal animals.
Applicant's summary and conclusion
- Conclusions:
- It was concluded, that for the assessment of systemic toxicity, oral administration of octahydro-4,7-methano-1H-indenedimethanol (TCD Alcohol DM), an industrial chemical intermediate, to RccHan™;WIST (Han Wistar) rats at dose levels of 250, 500 and 1000 mg/kg/day for 13 weeks the no-observed-adverse-effectlevel (NOAEL) in this study was considered to be 1000 mg/kg/day, and there were no adverse effects noted on the male and female reproduction organs, oestrous cycle, and sperm parameters.
It is acknowledged that adverse treatment related changes with TCD Alcohol DM were seen in the nose/turbinates of all treated groups of both sexes. Nasal findings comprised of inflammatory exudate in the lumen of the nasal cavity and nasopharynx,
degeneration/regeneration/inflammatory cell infiltration of the epithelium and deformity/fusion of turbinates. This pathology was considered to
be secondary to retrograde aspiration of material from the oropharynx into the nasopharynx and nasal cavity, this is considered to be a local effect, associated with the route of administration of this formulation and as such has been excluded from the assessment of systemic toxicity. - Executive summary:
The systemic toxic potential of TCD Alcohol DM, to Han Wistar (RccHanTM:WIST) rats by oral gavage administration was assessed over a period of 13 weeks. Three groups, each comprising ten males and ten females, received TCD Alcohol DM at doses of 250, 500 or 1000 mg/kg/day. A similarly constituted control group received the vehicle, 16% (w/w) ethylacetate in propylene glycol, at the same volume dose as the treated groups.
During the study, clinical condition, detailed physical and arena observations, sensory reactivity, grip strength, motor activity, body weight, food consumption, ophthalmoscopy, haematology (peripheral blood), blood chemistry, oestrous cycles, sperm analysis, organ weight, macropathology and histopathology investigations were undertaken.
Results:
Three females receiving 1000 mg/kg/day were killed for welfare reasons an say 12, 13 and 80 due to marked breathing impairment. Clinical signs prior to despatch included laboured/ shallow/irregular/slow breathing, räles (wet), decreased activity, piloerection, elevated gait, excessive chewing and distended abdomen. Macroscopic examination revealed abnormal contents (gas) and/or distension of the caecum, colon, ileum, jejunum, stomach and/or incomplete lung collapse in each of these animals with no direct histopathologic findings but associated with the histopathological changes in the nasal turbinates detailed in the following paragraph. The following section includes additional macropathology and histopathological examination findings: No. 132, minimal haemorrhage that correlated to dark, multilobular, diffuse areas of the Jungs and minimal apoptosis of the thymus correlating to dark thymus areas; No. 136, small spieen within no microscopic correlate, minimal lung and bronchi perivascular cell infiltrate and inflammation, minimal apoptosis of the thymus correlating to dark thymus areas; No. 140, minimal apoptosis and decreased cellularity of the thymus with no macroscopic correlate and a small spieen with slight white pulp atrophy observed microscopically.
Microscopic findings were seen in the nose and comprised of inflammatory exudate in the lumen of the nasal cavity and nasopharynx, degeneration/regeneration/inflammatory cell infiltration of the epithelium and, deformity/fusion of turbinates. The microscopic changes in the nose/turbinates in two of the decedents (No. 132, 140) were of a severity to conclude that they were the factor responsible for the death whereas in the remaining animal (No. 136) these findings were not of a severity to be certain as to the cause of death. Similar findings in the nose/turbinates were also seen in terminal animals.
Signs associated with dosing included räles and rapid breathing in individual animals at 500 or 1000 mg/kg/day during treatment. It is considered that this sign is predominately related to the dosing procedure and potential reflux of the formulation, rather than a systemic effect of treatment. Similar signs have been observed at physical examination in a few treated animals.
There were no treatment-related findings at the sensory reactivity, grip strength or motor activity investigations. Oestrous cycles were also considered unaffected by treatment.
Body weight change and food consumption was unaffected by treatment with TCD Alcohol DM.
There were no treatment-related ophthalmoscopic findings.
During Week 13 of treatment haematological investigations revealed a shortening of activated partial thromboplastin times in males receiving 250, 500 or 1000 mg/kg/day and to a lesser degree in females receiving 500 or 1000 mg/kg/day. In addition, blood chemistry examination revealed slightly high alkaline phosphatase activities in males receiving 1000 mg/kg/day, although in the absence of any change in associated parameters (ALT and AST), the significance of this is unclear and also slightly high cholesterol concentration in these males.
Organ weight changes that were considered to be related to treatment were high absolute and body weight-adjusted liver weights in males and females at 500 or 1000 mg/kg/day, and high body weight-adjusted kidney weight in males with a dose-relationship apparent (absolute kidney weights were also slightly high) and females given 1000 mg/kg/day. In addition, there were high body weight-adjusted spieen weights in males given 1000 mg/kg/day.
There was no effect of treatment an sperm motility, morphology or concentration. There were no treatment-related macroscopic findings.
Treatment related microscopic changes were seen in the nose/turbinates of all treated groups. Findings comprised of inflammatory exudate in the lumen of the nasal cavity and nasopharynx, degeneration/regeneration/inflammatory cell infiltration of the epithelium and deformity/fusion of turbinates. In addition, epithelial hyperplasia of the non-glandular stomach was seen in occasional animals of both sexes given 500 and 1000 mg/kg/day and a single male given 250 mg/kg/day. A single case of erosion was seen in the non-glandular region of the stomach of a female given 1000 mg/kg/day, although these changes were of an uncertain relationship to treatment with TCD Alcohol DM.
Conclusion:
It was concluded, that for the assessment of systemic toxicity, oral administration of TCD Alcohol DM, an industrial chemical intermediate, to RccHanTM;WIST (Han Wistar) rats at dose levels of 250, 500 and 1000 mg/kg/day for 13 weeks the no-observed-adverse-effect-level (NOAEL) in this study was considered to be 1000 mg/kg/day.
It is acknowledged that adverse treatment related changes with TCD Alcohol DM were seen in the nose/turbinates of all treated groups of both sexes. Nasal findings comprised of inflammatory exudate in the lumen of the nasal cavity and nasopharynx, degeneration/regeneration/inflammatory cell infiltration of the epithelium and deformity/fusion of turbinates. This pathology was considered to be secondary to retrograde aspiration of material from the oropharynx into the nasopharynx and nasal cavity, this is considered to be a local effect, associated with the route of administration of this formulation and as such has been excluded from the assessment of systemic toxicity.
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