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EC number: 221-259-8 | CAS number: 3048-64-4
- 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
Based on the 14-wk inhalation study, the NOAEL for repeated inhalation toxicity in the rat is 24.8 ppm (122 mg/m3). These values are based on systemic effects other than thyroid and kidney that are not considered relevant to humans (IARC, 1998).
Key value for chemical safety assessment
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
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Remarks:
- GLP test according to guideline. The test report from the Japanese Ministry of Health & Welfare is not available, but all the data were validated by the Japanese authorities within the OECD SIDS program Information in this record is from therefore from the SIDS dossier, a reliable secondary source, and used as supportive information. Reliability assessment based on that given in SIDS dossier.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Principles of method if other than guideline:
- No further information available.
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- other: CrjCD (SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
Individual rats were identified by ear tattoo and cage cards.
- Age at study initiation: 5 weeks
- Diet (e.g. ad libitum): rat chow diet was provided ad libitum.
- Water (e.g. ad libitum): Water was provided ad libitum
- Housing: Rats were housed individually in suspended wire mesh metallic cages
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24 0C
- Humidity (%): 31-79%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hour light-dark cycle. - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- Doses of test article were administered by gavage in corn oil once/day at 5.0 ml/kg.
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- once daily
- Dose / conc.:
- 4 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 20 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 14 M, 14 F control and high dose, 7 M, 7 F mid and low dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Post-exposure period: 14 days
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observations for mortality, morbidity and clinical signs were made at least once a day.
BODY WEIGHT: Yes
- Time schedule for examinations: Body wt was determined at initiation and on dosing days 2, 5, 7, 10, 14, 21, and 28 and recovery days 2, 5, 7, 14 and at necropsy.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption was determined at initiation and on dosing days 2, 5, 7, 10, 14, 21, and 28 and recovery days 2, 5, 7, 14 and at necropsy.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Water consumption was determined and unfasted urines were collected during dosing days 25-26 and recovery days 11-12.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Hematological analysis was conducted on day 29 and on day 15 of recovery.
- Parameters checked: Parameters examined were RBC, Hct, Hb, MCV, MCH, MCHC, platelets, reticulocytes, three coagulation factors, WBC and differential counts.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Hematological analysis and clinical chemistries were conducted on day 29 and on day 15 of recovery.
- Parameters checked: GOT, GPT, Al-P, LDH, gamma-GTP, glucose, total cholesterol, triglycerides, bilirubin, BUN, creatinine, sodium, potassium, chloride, calcium, inorganic phosphate, total protein, albumin, and protein fractionation.
URINALYSIS: Yes
- Parameters checked: Urine was analyzed for pH, protein, glucose, ketones, urobilinogen, bilirubin, occult blood, color, sediment, volume, specific gravity, sodium, potassium, chloride, calcium, and inorganic phosphates. - Sacrifice and pathology:
- At end of dosing and on day 15 of recovery, rats were sacrificed
GROSS PATHOLOGY: Yes, Brain, pituitary, thymus, thyroid, parathyroid, lung, heart, liver, kidneys, spleen, adrenal glands, testes and ovaries were weighed before fixation.
HISTOPATHOLOGY: Yes, 46 tissues/organs were fixed and prepared for histopathologic examination: liver, kidneys, spleen, heart, lung, brain, pituitary, adrenal glands, thyroid, parathyroid, thymus, mesenteric lymph nodes, pancreas, tongue, mandibular lymph nodes, submandibular gland, sublingual gland, parotid gland, zymbal gland, skin, sternum, femur, spine, skeletal muscle, thoracic aorta, pharynx, trachea, bronchi, esophagus, stomach, duodenum, jejunum, ileum, caecum, colon, rectum, bladder, seminal vesicle, prostate, ovary, uterus, vagina, ischiatic nerve, testes, epididymides, eye and Hardarian gland. - Statistics:
- Bartlett's test and analysis of variance as necessary and Dunnett's test. Kruskal-Wallis and Mann-Whitney U-test for histopathology.
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Description (incidence):
- There were no deaths attributable to test article administration.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At dosage termination, mean body wt was significantly reduced in high dose males but not in the recovery group;
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- There was no effect on food consumption.
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- In high dose males water consumption was decreased, however this changes were not seen after the recovery period.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Clinical chemistry showed a significant increase in albumin in both sexes at the highest dose that was not present after recovery. Males showed a decrease in alpha-1-globulin at the 20 and 100 mg/kg dose levels that was not present in recovery animals.
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In high dose males, urine protein was increased, however these changes were not seen after the recovery period.
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- In high dose males there was increased brain/body wt ratio and increased kidney/body wt ratio; both effects were absent in recovery males.
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Histopathology showed increased hyaline droplets in renal tubule epithelium of all male rats in the 20 and 100 mg/kg groups. Thyroid effects were hypertrophy of follicular cells, decreased colloid and irregular follicular shape in 6 males, 1 female in 100 mg/kg group, 1 male each in 20 and 4 mg/kg groups. These thyroid effects were not seen in any recovery animals.
- Dose descriptor:
- NOAEL
- Effect level:
- < 4 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
- Remarks on result:
- other: effects seen at 4 and 20mg/kg considered not relevant to humans
- Dose descriptor:
- NOAEL
- Effect level:
- 20 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- water consumption and compound intake
- Remarks on result:
- other: similar effects also seen in males
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 4 mg/kg bw/day (actual dose received)
- System:
- endocrine system
- Organ:
- thyroid gland
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- no
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 20 mg/kg bw/day (nominal)
- System:
- urinary
- Organ:
- kidney
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- no
- Conclusions:
- Hyaline droplets in the renal tubular epithelium, hypertrophy and irregular shape of follicular cells and decreased colloid in the thyroid, were observed in male rats at doses of 4 mg/kg/day and higher. The kidney effects are likely due to the male-rat-specific alpha 2u globulin accumulation. Increa ed albumin, and hypertrophy of follicular cells and decreased colloid in thyroid were found in the female 100 mg/kg/day group. Thyroid effects are reversible in both sexes. Therefore, the oral NOAEL for systemic effects other than thyroid and kidney is 20 mg/kg/day, based on reduced body we ght of females in the 100 mg/kg/day group.
- Executive summary:
A rat 28-day repeated oral dose toxicity test was conducted under the guidelines of the Japanese government (MHLW, Japan, 2000) using the close structural analogue ethylidene trinorbornene. Sprague-Dawley rats (7 animals/sex/dose with recovery groups of 7 additional animals/sex for the control and high dose groups held an additional 14-d) received doses of 0, 4, 20 and 100 mg/kg/day for 28-d by oral gavage. In the 100 mg/kg group females the mean body weight was significantly reduced at dosage termination but not in the recovery group. Food consumption was not affected. Urinalysis revealed an increase in the number of animals with protein-positive urine and a decrease in water consumption in males given 100 mg/kg. These changes were not found at the end of recovery period. In the hematological examination, no effect was observed after administration of ENB. In the blood biochemical examination, 20 and 100 mg/kg group males showed a decrease in alpha-1 globulin level. However, these changes were not found at the end of the recovery period. In high dose males there was increased brain/body wt ratio and increased kidney/body wt ratio; both effects were absent in recovery males. At autopsy, pale discoloration of the kidneys was observed in males given 100 mg/kg, and histopathology showed increased hyaline droplets in renal tubule epithelium of all male rats in the 20 and 100 mg/kg groups. Histopathological examination of the thyroid indicated hypertrophy of follicular epithelium, as well as decrease in colloid or irregular shape of follicles in males given 4 mg/kg or more. Hypertrophy of follicular epithelium and decrease in colloid were also observed in females given 100 mg/kg. There were no effects on the testes. The NOAEL of ENB for repeated dose toxicity was reported to be less than 4 mg/kg/day for males (based on thyroid effects at 4 mg/kg and kidney effects at 20 mg/kg) and 20 mg/kg/day for females (based on thyroid effects at 100 mg/kg). However, the male rat kidney effects are consistent with alpha-2u-globulin nephropathy and are not considered to be relevant to humans (IARC, 1998). The thyroid effects are also likely to be a species specific effect not relevant to humans (IARC, 1998). For these reasons, the oral NOAEL based on systemic effects other than thyroid and kidney is 20 mg/kg/d, based on reduced body weight of females in the 100 mg/kg/d group.
This result can be considered representative of the likely toxicological effects of the close structural analogue vinyl norbornene.
Reference
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 20 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Remarks:
- Guideline study to GLP but original study report not available.
- Principles of method if other than guideline:
- This study was conducted to meet the criteria of the following guidelines: Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), Toxic Substances Control Act (TSCA), Food and Drug Administration (FDA), Organisation for Economic Co-operation and Development (OECD), Ministry of Agriculture, Forestry and Fisheries (MAFF), and European Economic Community (EEC).
- GLP compliance:
- yes
- Remarks:
- Test laboratory not specified in publication but thought to be Union Carbide Corporation, USA
- Limit test:
- no
- Species:
- rat
- Strain:
- other: CDF
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Each rat was uniquely numbered by toe-clipping.
TEST ANIMALS
- Source: Charles River Laboratories (Kingston, NY).
- Age at study initiation: 28 days
- Housing: individually in wire-mesh cages
- Diet: powdered, certified AGWAY~ PROLAB~ Animal Diet (Agway Inc.) ad libitum during non-exposure periods.
- Water: tapwater.
- Acclimation period: The animals were acclimated to the exposure chamber for two days prior to start of the exposures.
ENVIRONMENTAL CONDITIONS
- The room temperature and relative humidity were monitored continuously.
- Temperature: 20.0-24.5°C.
- Relative humidity: 40-64%
- Photoperiod: 12-hour. - Route of administration:
- inhalation: vapour
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: unchanged (no vehicle)
- Remarks on MMAD:
- MMAD / GSD: Not applicable
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel chambers with glass windows; The volume of each chamber was approximately 900 liters
- System of generating particulates/aerosols: Liquid ENB was metered from syringe pumps. The temperature in each evaporator was maintained at a level sufficient to vaporize the test substance (33-77 Celsius).
-
- Air flow rate: 200 liters/minute
- Air change rate: (approximately 13 air changes per hour). - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Chamber concentrations of ENB vapor were analyzed by gas chromatography. At least two samples per hour were obtained from each exposure chamber and the control chamber. Analysis was by GC/FID
- Duration of treatment / exposure:
- At least 13 weeks. During the 14th week, the males and females (including those animals designated for perfusion-fixation) received two and three consecutive days of exposure, respectively. The animals assigned to the recovery period were exposed three consecutive days during the 14th week.
- Frequency of treatment:
- 6 hours per day, 5 days per week. Total exposures males, 66; females 67.
- Dose / conc.:
- 5 ppm (analytical)
- Remarks:
- equivalent to 24mg/m3
- Dose / conc.:
- 25 ppm (analytical)
- Remarks:
- equivalent to 122mg/m3
- Dose / conc.:
- 149 mg/m³ air (analytical)
- Remarks:
- equivalent to 732mg/m3. Target was 150ppm.
- No. of animals per sex per dose:
- 15 male and 15 female
- Control animals:
- other: yes, filtered air
- Details on study design:
- Animals were assigned to three exposure groups and an air-exposed control group. Fifteen male and 15 female rats were assigned to each group. 10 animals from each sex group were sacrificed during week 14 and the remaining 5 males, 5 females per group followed for 4-wk recovery period with no exposure before sacrifice.
- Positive control:
- No
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were individually observed for signs of toxic effects except during the exposures. During the exposures, observations were recorded on a group basis. Preceding and following each exposure, observations were recorded for animals exhibiting clinical signs. On nonexposure days and during the recovery period, animals were observed once a day for clinical signs.
BODY WEIGHT: Yes
- All animals were weighedprior to the first exposure. The animals were weighed weekly.The animals assigned to the 4-week recovery period were weighed once a week and immediately prior to sacrifice.
FOOD AND WATER CONSUMPTION:
- Food and water consumptions were measured weekly for all rats during the exposure regimen and the 4-week recovery period.
HAEMATOLOGY: Yes
- Parameters checked: total leukocyte count, erythrocyte count, hematocrit, hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin, concentration (MCHC), platelet count, prothrombin time, activated partial, thromboplastin time
CLINICAL CHEMISTRY: Yes
- Parameters checked: glucose, urea nitrogen, creatinine, total protein, albumin, globulin, total, conjugated, and unconjugated, bilirubin, calcium, phosphorus, sodium, potassium, chloride, total cholesterol, Free T3, Total T3, T3 uptake, Free T4, Total T4, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), lactate dehydrogenase (LOH), gamma-glutamyl transferase (GGT), sorbitol dehydrogenase (SOH), alkaline phosphatase (ALK), glutamate dehydrogenase (GLOH). Thyroid hormones were measured by commercially available RIA.
URINALYSIS: Yes
- Parameters checked: urine volume, appearance, sediment (microscopic), protein, potassium, osmolality, pH, occult blood, glucose, creatinine, chloride, protein, bilirubin, urobilinogen, ketones, sodium - Sacrifice and pathology:
- The male and female animals were sacrificed after 66 and 67 exposures respectively. Rats were killed by exsanguination via the brachial blood vessels following anesthesia with methoxyflurane.
GROSS PATHOLOGY: Yes, The brain, liver, kidneys, lungs, spleen, heart, thymus, pituitary, thyroid (weighed after fixation), adrenal glands from all animals, and testes from all males were weighed at sacrifice.
HISTOPATHOLOGY: Yes, Selected tissues were fixed in 10% neutral buffered formalin. (except for eyes and testes which were fixed in Bouin's solution). - Other examinations:
- Morphometric analysis was conducted on thyroids from 10 males in the control and all exposure groups. Morphometric studies were performed to measure changes in the quantity of follicular colloid of the thyroid glands.- Statistics:
- Quantitative continuous variables were intercompared between ENB groups and the corresponding air-control groups using Bartlett's homogeneity of variance, analysis of variance, and Duncan's multiple range tests. Non-parametric data were statistically analyzed using the Kruskall-Wallis test followed by the Mann-Whitney U test. A fiducial limit of <0.05(two-tailed)was used as the critical level of significance for all comparisons.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Periocular swelling and/or encrustation was seen in females of all groups and males of the 149 ppm group. Corneal dystrophy (linear opacity) was seen with equal frequency in both ENB and air control groups.
- Mortality:
- no mortality observed
- Description (incidence):
- No animals died during the study.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no effects on absolute body weight gain. Body weight gains for the 24.8 and 149 ppm groups of male rats were 13% and 21% lower, respectively, than the controls at the end of the first exposure week, with subsequent recovery.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- During the 14-wk exposure, food consumption was increased in the 149 ppm group for most periods for males and females and remained increased during the recovery period compared to controls.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- Water consumption was increased in both males and females in the 149 ppm group during exposure and recovery periods. Increases ranged from 4.9 to 23.3% for males and -1.8 to 17.6% for females during exposure and from 14.9 to 20% for males and from 2.6 to 13.1% for females during the recovery period.
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Top dose males had statistically significantly decreased erythrocyte count, hemoglobin concentration, and hematocrit; increased MCHC was seen in the middle dose . Males in the low dose group had decreased erythrocyte count and hematocrit, with increased MCHC. No statistically significant effects were seen in the recovery group.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Other than small changes in certain thyroid hormone concentrations there were no statistically significant effects on serum chemistry. Serum T3 uptake was slightly reduced, with statistical significance, in 24.8 and 149 ppm group males at the 14-wk sacrifice, but not at the recovery sacrifice. Serum T4 was significantly raised in middle-dose males in the 9 day study at not significantly at the top dose.
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The only findings were statistically significant decreased urine osmolality (15%) and creatinine (20.8%) at the 14-wk sacrifice, but not the recovery sacrifice, in the male rats exposed to 149 ppm ENB.
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Relative liver weights were increased only in the 149 ppm males. Relative kidney weights were increased for males of all treatment groups and females exposed to 149 ppm ENB. Absolute and relative thyroid gland weights were increased for males of the middle- and top-dose groups in the 9-day study. There were no effects on thyroid gland weight in the subchronic study.
- Gross pathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Other than the thyroid gland, no exposure related lesions were observed. Principal target organ effects were to the thyroid gland, which showed an exposure concentration-related, but not exposure time-related, depletion of follicular colloid that resolved during the recovery period. There was light microscopic evidence for a hypertrophic and hyperplastic response in the follicular epithelium that resolved more slowly. The thyroid colloid depletion was a graded effect without a clear no-effect concentration, but was not accompanied by any clinical or clear biochemical evidence for thyroid dysfunction. The depletion was generally not seen in the recovery animals. A no-effect concentration of 4.9 ppm was established for the follicular cytological effects.
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- ACHIEVED EXPOSURES
Means of levels determined at 5 sites in the chamber were 4.27 +/- 0.28, 24.5 +/- 098 and 150 +/- 5.1 ppm with coefficients of variation of 6.6, 4.0 and 3.4% around the target concentrations (5, 25 and 150 ppm) indicating a uniform ENB vapour distribution. - Dose descriptor:
- NOAEC
- Effect level:
- 5 ppm (analytical)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical biochemistry
- histopathology: non-neoplastic
- Dose descriptor:
- NOAEC
- Effect level:
- 25 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- organ weights and organ / body weight ratios
- urinalysis
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 5 ppm (analytical)
- System:
- endocrine system
- Organ:
- thyroid gland
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- no
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 149 ppm (analytical)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 149 ppm (analytical)
- System:
- urinary
- Organ:
- kidney
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
- Conclusions:
- Exposure of rats to ENB at 5, 25 and 150 ppm for 13+ weeks produced no mortality and minor systemic toxicity. No histopathologic findings, other than in the thyroid gland, were found. A no-effect concentration of 4.9 ppm ENB was established for the follicular cytological effects. The NOAEL for effects other than thyroid is 25 ppm (122 mg/m3).
- Executive summary:
Ballantyne et al. (1997) published a 14-week guidenline inhalation study of the structural analogue ethylidene norbornene in rats conducted according to GLP. CDF rats (15/sex/dose) were exposed to analytically measured ENB vapor concentrations of 0, 5, 25, or 149 ppm (0, 24, 122, 732 mg/m3, respectively) for 6 hr/day, 5 days/week for 13+ weeks (a total of 67 exposures). No deaths occurred during the study. Overall, toxicity was greater in males than in females. Clinical chemistries were unaffected with the exception of reduced tri-iodothyronine (T3) uptake in males of the 25 and 149 ppm groups at 14 wk by not after the 4-wk recovery. T3 uptake was slightly reduced (not statistically significant) in male rats of the 5 ppm exposed group only at 14 wk. Urine osmolality and creatinine were decreased in males of the 149 ppm group at wk 14, but not in the recovery animals. Urine protein was increased in the 149 ppm exposed females at 14 wk and after the 4-wk recovery. Relative kidney weights increased in all groups of males and the females exposed to 149 ppm ENB. Relative kidney weights were increased (not statistically significant) in 149 ppm exposed males at the end of the 4-wk recovery period. Relative liver weight was increased in 149 ppm exposed males, and also at the end of the recovery period. Relative liver weight was increased in 149 ppm exposed females only after the recovery period. Principal target organ effects were to the thyroid gland, which showed an exposure concentration-related, but not exposure time-related, depletion of follicular colloid that resolved during the recovery period in all exposed groups except the 5 ppm exposed females. There was light microscopic evidence for a hypertrophic and hyperplastic response in the follicular epithelium that resolved more slowly. The thyroid colloid depletion was a graded effect without a clear no-effect concentration, but was not accompanied by any clinical or clear biochemical evidence for thyroid dysfunction. The depletion was generally not seen in the recovery animals. A no-effect concentration of 5 ppm (24 mg/m3) was established for the follicular cytological effects. Other than the thyroid gland, no exposure related lesions were observed following histopathology, therefore, for effects other than thyroid, the NOAEL is 25 ppm (122 mg/m3) based on changes in organ weights and urinalysis findings observed at 149 ppm (732 mg/m3). This result can be considered representative of the likely toxicological effects of the close structural analogue vinyl norbornene.
Reference
Morphometry: A statistically significant reduction in mean colloid area per follicle was measured in rats of the high dose group (150 ppm) as compared to control group animals. There were no significant changes in the mean colloid area of recovery group animals of the high concentration group.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEC
- 122 mg/m³
- Study duration:
- subchronic
- Species:
- rat
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
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
There are no repeat dose studies available for vinyl norbornene.
In a sub-acute 28-day repeated oral dose toxicity test using the close structural analogue ethylidene trinorbornene (ENB), Sprague-Dawley rats received doses of 0, 4, 20 and 100 mg/kg/day for 28-d by oral gavage. In the 100 mg/kg group females the mean body weight was significantly reduced at dosage termination but not in the recovery group. Food consumption was not affected. Urinalysis revealed an increase in the number of animals with protein-positive urine and a decrease in water consumption in males given 100 mg/kg. These changes were not found at the end of recovery period. In the hematological examination, no effect was observed after administration of ENB. In the blood biochemical examination, 20 and 100 mg/kg group males showed a decrease in alpha-1 globulin level. However, these changes were not found at the end of the recovery period. In high dose males there was increased brain/body wt ratio and increased kidney/body wt ratio; both effects were absent in recovery males. At autopsy, pale discoloration of the kidneys was observed in males given 100 mg/kg, and histopathology showed increased hyaline droplets in renal tubule epithelium of all male rats in the 20 and 100 mg/kg groups. Histopathological examination of the thyroid indicated hypertrophy of follicular epithelium, as well as decrease in colloid or irregular shape of follicles in males given 4 mg/kg or more. Hypertrophy of follicular epithelium and decrease in colloid were also observed in females given 100 mg/kg. There were no effects on the testes. The NOAEL of ENB for repeated dose toxicity was reported to be less than 4 mg/kg/day for males (based on thyroid effects at 4 mg/kg and kidney effects at 20 mg/kg) and 20 mg/kg/day for females (based on thyroid effects at 100 mg/kg). However, the male rat kidney effects are consistent with alpha-2u-globulin nephropathy and are not considered to be relevant to humans (IARC, 1998). The thyroid effects are also likely to be a species specific effect not relevant to humans (IARC, 1998). For these reasons, the oral NOAEL based on systemic effects other than thyroid and kidney is 20 mg/kg/d, based on reduced body weight of females in the 100 mg/kg/d group.
There are reliable sub-chronic studies using the inhalation route on the close structural analogue ENB. The early studies, with limited monitoring, showed that exposure to high concentrations (e.g., 237 ppm) of ENB vapor produced liver, kidney, and testicular injury in the rat accompanied by a high incidence of mortality, and liver and testicular injury in the dog (Kinkead, E. et al., 1971). In the more recent rat study where the purity of the ENB was measured and exposure concentrations maintained at or below 149 ppm, there is no biochemical or histologic evidence for testicular effects, minor adaptive and reversible changes in the liver, and male-rat specific kidney effects (Ballantyne, B. et al., US, 1997). Thyroid effects were evaluated in the Ballantyne study and are considered likely to be a species specific effect not relevant to humans.
Based on the 14-wk inhalation study, the NOAEL for repeated inhalation toxicity in the rat is 24.8 ppm (122 mg/m3). These values are based on systemic effects other than thyroid and kidney, which are not relevant to humans (IARC, 1998).
There is no study in VNB or any identified structural analogue by the dermal route.
Justification for selection of repeated dose toxicity via oral
route - systemic effects endpoint:
Based on read across to a similar substance.
Justification for selection of repeated dose toxicity inhalation -
systemic effects endpoint:
Most recent study selected. Study conducted under well-designed
protocol, analytical purity of the test material reported, and detailed
information on study available.
Repeated dose toxicity: inhalation - systemic effects (target organ)
digestive: liver; urogenital: kidneys
Justification for classification or non-classification
On the basis of reliable animal data, no effects have been observed which warrant classification under directive 67/548.
Under regulation 1272/2008, a classification for STOT (RE) category 2 could be considered appropriate as a LOAEL of 0.75mg/l (150ppm) was established in a sub-chronic study. However, the only effects seen were increases in liver and kidney weight without associated changes to histopathology and changes to urinary parameters of unknown toxicological significance. Other effects noted at this or lower concentrations (e.g. on the thyroid) were established as reversible. Therefore no 'significant' toxic effects were seen and therefore classification under 1272/2008 is not warranted based on this study. However, the data from older studies reported adverse findings (LOAEL) of 61ppm (0.305mg/l) in both rats and dogs. These changes were associated with adverse histopathology as well. These findings could be considered 'significant' and therefore, on a precautionary basis, a STOT(RE) classification (category 2) would appear warranted based on the principal of read across from the results from ethylidene norbornene to the structurally similar vinyl norbornene.
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