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EC number: 208-594-5 | CAS number: 534-22-5
- 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
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:
- supporting study
- Study period:
- not specified
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- not specified in the publication
- GLP compliance:
- not specified
- Limit test:
- no
- Specific details on test material used for the study:
- not specified
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- Test animals:
- Source: Charles River Laboratories Inc. (St. Constant, QC)
- Age: 5 to 6 weeks
- acclimatization: for 12 days before being randomized and assigned to a particular dose group
- acclimatized for 12 days before being randomized and assigned
- Number: 10 per group
- Housing: 2 per cage
- Diet: ad libitum access to Purina Rodent Chow 5001
- Water: ad libitum city tap water
Environmental conditions:
- Temperature:18 to 26°C and
- Humidity: 30 to 70%, monitored continuously - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- The test item was administered in corn oil at a maximum volume of 5.0ml/kg bw.
The animals were weighed daily prior to gavage.
Food consumption was measured on a weekly basis. - Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- Previous studies have demonstrated the stability of furan dosing formulations for at least 14 days under the conditions of the test
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Animals were gavaged daily (7 days/week)
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 0.4 mg/kg bw/day (nominal)
- Dose / conc.:
- 1.5 mg/kg bw/day (nominal)
- Dose / conc.:
- 3 mg/kg bw/day (nominal)
- Dose / conc.:
- 6 mg/kg bw/day (nominal)
- Dose / conc.:
- 12 mg/kg bw/day (nominal)
- Dose / conc.:
- 25 mg/kg bw/day (nominal)
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 200 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10 per dose group
- Control animals:
- yes
- Details on study design:
- - Each dose was prepared separately on a volume-to-weight (v:w) ratio
- Dosing solutions were stored in a refrigerator at 4°C.
- Fresh solutions were prepared every 14 days.
- Rats were identified by tail markings
- Sentinel animals for health surveillance were housed in the same room as study animals and remained disease-free throughout the study
Dose selection rationale:
Previous study with the doses of 50.0, 100.0, and 200.0 mg/kg bw/day revealed to be too elevated and resulted in either death (24 hr) or poor health of animals (48 hr). - Positive control:
- not specified
- Observations and examinations performed and frequency:
- Animals were observed for signs of illness twice daily during week days and once daily on weekends and holidays
- Sacrifice and pathology:
- At the end of the study, each animal was killed by exsanguination via the abdominal aorta under isofluorane anesthesia and a complete gross examination was performed. Liver, heart, kidneys, thymus, spleen, stomach, thyroid, adrenals, pancreas, testes, epididymides, prostate, and seminal vesicles were collected for histological examination.
Only the control and 25.0 mg/kg bw/day dose groups were examined for the stomach, thyroid, parathyroid (when present in thyroid section),
adrenals, thymus, spleen, pancreas, testes, epididymides, prostate, seminal vesicles, and heart. - Other examinations:
- Analysis of Serum Clinical Biochemistry:
At the time of sacrifice, blood from the abdominal aorta was collected. The measured markers were serum amylase (U/L), albumin (g/L),
alkaline phosphatase (ALP-U/L), alanine transaminase (ALTU/L), aspartate transaminase (AST-U/L), bicarbonate (mmol/L), total bilirubin (mmol/L),
calcium (mmol/L), chloride (mmol/L), cholesterol (mmol/L), creatinine (mmol/L), creatine kinase (U/L), glucose (mmol/L), lipase (U/L), magnesium
(mmol/L), phosphorous (mmol/L), potassium (mmol/L), sodium (mmol/L), sodium:potassium ratio, total protein (TP-g/L), triglycerides
(mmol/L), thyroxine (T4-nmol/L), triiodothyronine (T3-nmol/L), uric acid (mmol/L), and urea (mmol/L).
Hematology and Flow Cytometry:
The following parameters were measured: red blood cell (RBC) count, hematocrit (HCT), hemoglobin (HGB), mean corpuscular volume (MCV),
mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red bloodcell distribution width (RDW),
platelet (PLT) count, mean platelet volume (MPV), total white blood cell (WBC) count, and differential counts of lymphocytes, monocytes, neutrophils,
eosinophils, and basophils. - Statistics:
- Bw, food consumption, clinical biochemistry, hematology, and organ weights were expressed as mean +/- standard deviation.
Statistical comparisons of control rats and 2-methylfuran treated rats were performed by one-way analysis of variance
(ANOVA) followed by Tukey’s multiple comparison test.
Linear trend analysis was also performed. A value of p < .05 was considered statistically significant. - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Animals dosed with 50.0 mg/kg bw/d were sacrificed after 48h due to an unhealthy appearance and marked weight loss compared to the control group.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Animals dosed with 100.0 and 200.0 mg/kg bw/d were found dead within 24h after the first dosing.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The animals at 25.0 mg/kg bw/day lost 7% bw compared to the control animals.
Although not statistically significant, there is a linear trend between the control and 25.0 mg/kg bw/day dose groups.
No other dose groups were affected. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- The observed decrease in bw at 25 mg/kg bw/day was accompanied by a significant decrease in food consumption.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- RBC count, HGB, HCT, and MCV were all significantly decreased (p < .05) at the 25.0 mg/kg bw/day dose, while RDW was significantly
increased (p < .05) at the 12.0 and 25.0 mg/kg bw/day dose groups.
PLT levels were significantly and dose dependently increased at the 6.0, 12.0, and 25.0 mg/kg bw/day doses (16%, 17%, and 24% increase, respectively, relative to controls).
The MCH showed a slight but significant trend to decrease at 25.0 mg/kg bw/day, while MCHC and MPV were not altered.
Total WBC count, and levels of basophils and eosinophils were not affected. However, there was a significant decreasing
trend for lymphocytes and significant increasing trends for neutrophils and monocytes. - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Physiological Markers:
Serum enzymes (ALT, AST, and ALP) indicative of liver injury were not significantly affected.
Total bilirubin levels increased with dose and differed significantly (p < .05) from controls at the 25.0 mg/kg bw/day dose.
Serum albumin levels were significantly increased (p < .05) at 6.0, 12.0, and 25.0 mg/kg bw/day doses.
Total protein was significantly increased (p < .05) at 12.0 and 25.0 mg/kg bw/day doses.
Cholesterol was significantly and dosedependently increased (p < .05) starting at 0.4 mg/kg bw/day.
Triglycerides showed a significant decrease (p < .05) starting at 3.0 mg/kg bw/day.
Serum amylase demonstrated a significant decrease (p < .05) starting at 1.5 mg/kg bw/day.
Creatinine showed a significant linear trend decrease starting at the 0.4 mg/kg bw/day dose group and dose-dependent significance
(p < .05) starting at the 6.0 mg/kg bw/day.
Creatine kinase showed a significant decreasing trend with dose.
Lipase showed a significant linear trend increase (p < .0001) with increasing dose.
No significant changes were seen in the levels of glucose, uric acid, and urea (last 2 parameters not shown).
Electrolyte Changes:
Phosphorus and calcium showed a significant increasing trend and differed significantly from controls at the 12.0 and 25.0 mg/kg bw/day doses (p < 0.05).
Sodium, potassium, Na:K ratio, chloride, and magnesium showed no change.
Bicarbonate levels did not differ significantly but showed a statistically significant linear increasing trend (0.04899) with dose. - Urinalysis findings:
- not examined
- 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):
- Some organ weights were significantly altered relative to bw.
Relative liver weights were significantly and dose dependently increased starting at 9% in the 3.0 mg/kg bw/day dose and reaching 42% in the 25.0 mg/kg bw/day dose group.
Relative spleen weights were increased at the higher doses, starting at 17% in the 6.0 mg/kg bw/day group and reaching 22% at the 25.0 mg/kg bw/day dose group.
The relative weight of the left kidney increased by approximately 6% at the 25.0 mg/kg bw/day group although this effect was not seen in the right kidney.
No other organ showed significant changes in relative or absolute weight.
There was a linear significant trend in decrease in relative prostate weight in the 25.0-mg/kg bw/day dose group.
It was decreased by approximately 20% compared to controls. - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Gross necropsy examination of the animals in the highest dose groups (200, 100 and 50 mg/kg bw/d) showed inflamed stomachs and gross changes in the liver. The left lateral and caudate lobes and papillary processes were most severly affected. Mild to very marked centrilobular necrosis, ranging from the involvement of a few zone 3 hepatocytes to necrosis of large areas of parnechyma.
Treatment-related gross pathology observations in other dose groups were restricted to the liver.
All animals of the 25.0-mg/kg bw/day dose group had mild changes in the left lateral lobe. Less consistently affected were the papillary processes (3 animals) and caudate lobe (4 animals).
Small white foci and/or small white slightly raised nodules were evident near the liver hilus in 6 animals.
Pale or yellow/green discoloration of the dorsal margin of the left lobe was noted in 5 animals of the 25.0-mg/kg bw/day group.
Two animals of the 12.0-mg/kg bw/day and 1 animal of the 6.0-mg/kg bw/day dose groups had small white foci on the dorsal margin of the left lateral lobe. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Histological lesions that increased in severity with dose were detected in the livers of the 1.5, 3.0, 6.0, 12.0, and
25.0 mg/kg bw/day dose groups.
Mild histological hepatic lesions of apoptotic hepatocytes, Kupffer cells with yellow pigment in the cytoplasm, and microfoci of inflammatory cell
infiltrate noted in the 1.5 mg/kg bw dose progress in severity with increasing dose group.
Initially being a subcapsular lesion, the above changes also appear periportal in the 12 and 25 mg/kg dose groups.
Mild interstitial fibrosis and oval cell hyperplasia first evident at 6.0 mg/kg, progress to mild to moderate, focal, subcapsular, and periportal cholangiofibrosis in the 12 and 25 mg/kg groups. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Gross and Histological Observations in Other Tissues:
A single incidental finding was observed in 1 animal of the 6.0 mg/kg bw/day dose group whose left testis was flaccid and about half the normal size.
The left epididymis was also smaller than normal. No changes were observed in any other tissues.
There was increased vacuolation in the zone fasciculata of the adrenals in the 25.0 mg/kg bw/day dose group.
In the control group, vacuolation was graded from mild (6 animals) to moderate (4 animals).
In the 25.0 mg/kg bw/day group, vacuolation was graded from mild (2 animals) to moderate (8 animals).
No dose-related gross observations or histological changes were seen in the other tissues examined, which included heart, lungs, kidneys, pancreas, prostate, seminal vesicles, testes, spleen, stomach, thyroid, or parathryoid (when found in the thyroid sections).
Endocrine Functions:
Total serum T4 levels were significantly increased (p < .05) only at 1.5 and 3.0 mg/kg bw/day but not at the higher doses, whereas T3 levels were significantly increased (p < .05) with dose starting at the 1.5 mg/kg bw/day dose group. - Details on results:
- The administration of 2-methylfuran resulted in significant increases in liver weights.
The observations of clinical chemistry suggest that exposure to 2-methylfuran affects both the hepatocytes
and the bile duct system in the liver. No significant changes were seen in the hepatic ‘‘leakage’’ enzymes ALT and ASP,
indicative of damage to the hepatocytes, nor in ALP, indicative of bile duct damage.
Statistically significant reductions in serum triglycerides were observed at 3.0 mg/kg bw/day and above which can be a biomarker of
hepatotoxicity, most frequently of hepatocellular necrosis.
Substantial, doserelated, and statistically significant increases were seen in the levels of cholesterol and bilirubin, which rose by 55% and
125%, respectively, at the 25.0 mg/kg bw/day dose.
Serum amylase was decreased significantly in a dosedependent manner starting at 1.5 mg/kg bw/day.
Both albumin and total protein levels were slightly statistically increased.
Levels of some of the electrolytes were altered. Phosphorus and calcium showed a linear increase with dose and were
increased significantly at 12.0 and 25.0 mg/kg bw/day. Sodium showed an increased linear trend with dose, although differences
among groups were small. Chloride, potassium, and magnesium showed no significant changes. No significant differences
were found in bicarbonate levels, but it showed a significant (0.04899) linear increase with dose.
Creatinine showed a consistently decreasing trend starting at the lowest dose. However, there were no histological
changes in either the left or the right kidney. The reduction in serum creatinine levels in this study could reflect an impaired ability
by the liver or kidneys (or both) to synthesize creatine.
Levels of T3 increased significantly and in a dose-related manner starting at 1.5 mg/kg bw/day, whereas T4 levels were
increased only at 1.5 and 3.0 mg/kg bw/day but not at the 3 highest doses.
Total WBC count did not change and there were no significant differences in the differential count, neutrophils and monocytes showed an increasing
trend and lymphocytes a decreasing trend.
A range of RBC parameters were significantly decreased at the highest dose (RBC, HGB, HCT, MCV). While MCH and
MCHC were also reduced at the highest dose, it was without statistical significance. The RDW was significantly increased
at the two highest doses, indicating an increase in the range of RBC size.
A significant increase in spleen weight in the 3 highest dose groups was observed. - Conclusions:
- In this 28-day gavage study in male Fischer 344 rats, the general toxicology findings affected tissue morphology, histopathology, clinical biochemistry, and hematology. The liver was the primary target organ that developed dose-dependent toxicity. Relative liver weights were increased by 42% at 25.0 mg/kg/body weight (bw)/day.
A NOAEL was not determined in this study. - Executive summary:
A 28-day gavage study in male Fischer 344 rats was performed. It was not specified if the study has been performed in accordance to a specific guideline nor if it was performed in compliance to GLP. However, based on the description it is concluded that the study was performed similar to a OECD TG 407 study.
The animals in the highest dose groups (200 and 100 mg/kg bw/d) were found dead within 24h after first dosing. Animals in the 50.0 mg/kg bw/d dose group were killed due to an unhealthy appearance and marked weight loss. Gross necropsy showed inflammation at the stomach and centrilobular necrosis of the liver.
The remainder of the study focused on the results of the lower dose groups: 0.4, 1.5, 3.0, 6.0, 12.0, and 25.0 mg/kg bw/day.
The general toxicology findings affected tissue morphology, histopathology, clinical biochemistry, and hematology. The liver was the primary target organ that developed dose-dependent toxicity. Relative liver weights were increased by 42% at 25.0 mg/kg/body weight (bw)/day. Histological changes in the liver were observed at 0.4, 1.5, 3.0, 6.0, 12.0, and 25.0 mg/kg bw/day. Although there were changes in the weights of other organs including prostate, kidneys, and spleen, these were not accompanied by histological changes.
These changes were not accompanied by clinical changes in the serum enzyme markers such as alanine transaminase, alkaline phosphatase, and aspartate transaminase. Clinical biochemistry markers for kidney were altered, but these were not accompanied by histological changes. The prostate was significantly decreased in size at the 25.0 mg/kg bw/day dose of 2-methyfuran. Some hematological parameters were also altered.
A NOAEL was not determined in this study. However, creatinine showed a consistently decreasing trend starting at the lowest
dose. The reduction in serum creatinine levels in this study could reflect an impaired ability by the liver or kidneys (or both) to synthesize creatine.
Reference
Body weight and food consumption in rats treated with 2-methylfuran
2-Methylfuran Dose (mg/kg bw/day) | p Value for Trend | |||||||
0 | 0.4 | 1.5 | 3.0 | 6.0 | 12.0 | 25 | ||
Body weight | 213.0±20.65 | 218.4 ± 12.74 | 219.7 ± 14.42 | 219.2 ± 12.08 | 213.4 ± 17.09 | 211.9 ± 16.0 | 198.1 ± 19.29 | 0.0219a |
Food (g) consumed/cage/day | 30.39 ± 2.15 | 32.07 ± 1.56 | 31.57 ± 1.80 | 31.69 ± 1.37 | 30.63 ± 1.45 | 31.45 ± 1.32 | 27.83 ± 2.38* | 0.0001 |
a Indicates linear trend
*Indicates p < .05 in Tukey’s Multiple Comparison Test
Organ weight as % body weight in rats treated with 2-methylfuran
2-Methylfuran Dose (mg/kg bw/day) | p Value for Trend | |||||||
Parameters | 0.0 | 0.4 | 1.5 | 3.0 | 6.0 | 12.0 | 25.0 | |
Liver | 3.91 ± 0.11 | 3.99 ± 0.13 | 4.05 ± 0.14 | 4.11 ± 0.19* | 4.6 ± 0.12* | 4.98 ± 0.10* | 5.54 ± 0.14* | 0.001a |
Spleen | 0.23 ± 0.023 | 0.23 ± 0.012 | 0.24 ± 0.013 | 0.24 ± 0.009 | 0.27 ± 0.013* | 0.26 ± 0.013* | 0.28 ± 0.009* | 0.001a |
Right Kidney | 0.31 ± 0.0098 | 0.31 ± 0.011 | 0.31 ± 0.013 | 0.31 ± 0.011 | 0.31 ± 0.004 | 0.32 ± 0.0097 | 0.32 ± 0.012 | 0.003a |
Left Kidney | 0.31 ± 0.012 | 0.31 ± 0.013 | 0.31 ± 0.008 | 0.31 ± 0.009 | 0.32 ± 0.001 | 0.32 ± 0.008 | 0.33 ± 0.015* | 0.001a |
Prostate | 0.083 ± 0.014 | 0.09 ± 0.016 | 0.085 ± 0.01 | 0.082 ± 0.009 | 0.80 ± 0.01 | 0.079 ± 0.02 | 0.067 ± 0.026* | 0.039a |
aIndicates linear trend
*Indicates p < .05 in Tukey’s Multiple Comparison Test
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
Additional information
Justification for classification or non-classification
A recent 28-day gavage study in male Fischer 344 is available (Santokh et al. 2014). The animals in the highest dose groups (200 and 100 mg/kg bw/d) were found dead within 24h after first dosing. Animals in the 50.0 mg/kg bw/d dose group were killed due to an unhealthy appearance and marked weight loss. Gross necropsy showed inflammation at the stomach and centrilobular necrosis of the liver.
The remainder of the study focused on the results of the lower dose groups: 0.4, 1.5, 3.0, 6.0, 12.0, and 25.0 mg/kg bw/day. The general toxicology findings affected tissue morphology, histopathology, clinical biochemistry, and hematology. The liver was the primary target organ that developed dose-dependent toxicity. Relative liver weights were increased by 42% at 25.0 mg/kg/body weight (bw)/day. Histological changes in the liver were observed at 0.4, 1.5, 3.0, 6.0, 12.0, and 25.0 mg/kg bw/day. Although there were changes in the weights of other organs including prostate, kidneys, and spleen, these were not accompanied by histological changes.
These changes were not accompanied by clinical changes in the serum enzyme markers such as alanine transaminase, alkaline phosphatase, and aspartate transaminase. Clinical biochemistry markers for kidney were altered, but these were not accompanied by histological changes. The prostate was significantly decreased in size at the 25.0 mg/kg bw/day dose of 2-methyfuran. Some hematological parameters were also altered.
A NOAEL was not determined in this study. However, creatinine showed a consistently decreasing trend starting at the lowest
dose. The reduction in serum creatinine levels in this study could reflect an impaired ability by the liver or kidneys (or both) to synthesize creatine.
Based on the findings of centrilobular necrosis in the liver of animals dosed 50 mg/kg bw/d, and in accordance with the criteria specified in Regulation No. 1272/2008 on classification, labelling and packaging of substances and mixtures (CLP) section 3.9.2, a classification as STOT-RE 2 is considered required.
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