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EC number: 204-661-8 | CAS number: 123-91-1
- 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:
- chronic toxicity: oral
- Remarks:
- combined repeated dose and carcinogenicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Four groups of rats (60 males and 60 females per group) were maintained on drinking water containing:
0, 0.01, 0.1 and 1.0% dioxane for up to 716 days. - GLP compliance:
- no
- Species:
- rat
- Strain:
- Sherman
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 6-8 weeks
- Diet: ad libitum
- Water: ad libitum
ENVIRONMENTAL CONDITIONS
No data - Route of administration:
- oral: drinking water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Drinking water was prepared by dilution in water (1%; 60 mL dioxane added to 5940 mL water).
The drinking water was prepared twice weekly during the first year, and weekly during the second year.
Periodically samples were taken from storage vessels and individual water dispensers, and analysed for dioxane content by gas chromatography. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Stock samples were analysed for impurities at 6 different times during the 2 years, by gas chromatography.
- Duration of treatment / exposure:
- 716 days
- Frequency of treatment:
- continuous
- Dose / conc.:
- 0.01 other: %
- Remarks:
- corresponding to 9.6 mg/kg bw/day (males) and 19 mg/kg bw/day (females)
- Dose / conc.:
- 0.1 other: %
- Remarks:
- corresponding to 94 mg/kg bw/day (males) and 148 mg/kg bw/day (females)
- Dose / conc.:
- 1 other: %
- Remarks:
- corresponding to 1015 mg/kg bw/day (males) and 1599 mg/kg bw/day (females)
- No. of animals per sex per dose:
- 60 male and 60 female rats/dose
- Control animals:
- yes, plain diet
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations:
twice weekly (first month)
weekly (month 2-7)
biweekly (afterwards)
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily water consumption was recorded daily during 3 periods:
days 1-113, days 114-198, and days 446-460
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: Yes
- Time schedule for collection of blood: no data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: no data
- Parameters checked in table were examined: packed cell volume, total erythrocyte count, Hb, and total and different white blood cell counts.
CLINICAL CHEMISTRY: No data
URINALYSIS: No data
NEUROBEHAVIOURAL EXAMINATION: No data - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, a complete gross pathologic examination was performed.
Organ weights of brain, liver, kidneys, testes, spleen, and heart were recorded.
HISTOPATHOLOGY: Yes
brain
bone and bone marrow
ovaries
pituitary gland
uterus
mesentric lymph nodes
heart
liver
pancreas
spleen
stomach
prostrate
colon
trachea
duodenum
kidneys
esophagus
jejunum
testes
lungs
spinal cord
adrenal gland
parathyroid gland
nasal turbinates
urinary bladder - Statistics:
- Student's t-test was used for heamatology parameters, and body and organ weights;
Fisher's Exact probability test was used for analysis of tumours;
Chi-Square contingency tables and Fisher's exact propability test was used for survival comparison. - Clinical signs:
- effects observed, treatment-related
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- The concentration of 1% 1,4-dioxane led within two to four months to a severe reduction of survival rates in both sexes, nearly half of the group succumbing after four months. The survival rate after four months was essentially the same for all groups.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Within 2 days after initiating the study the body weights of both sexes at 1.0% 1,4-dioxane were significantly lower than controls. The body weights remained depressed throughout the study.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No effects on haematology were observed.
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Significantly increased liver weight in rats receiving 1% 1,4-dioxane.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In rats at 0.1 and 1.0% 1,4-dioxane, gross and histopathological examination revealed variable degrees of renal tubular epithelial and hepatocellular degeneration and necrosis, accompanied by regenerative activities in the liver (hepatocellular hyperplastic nodule formation) and renal tubuli. No effects were seen on male and female reproductive organs.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- In rats at 0.1 and 1.0% 1,4-dioxane, gross and histopathological examination revealed variable degrees of renal tubular epithelial and hepatocellular degeneration and necrosis, accompanied by regenerative activities in the liver (hepatocellular hyperplastic nodule formation) and renal tubuli. No effects were seen on male and female reproductive organs.
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Male and female rats receiving 0.1% (equivalent to 94 and 148 mg/kg/day respectively) and 0.01 % (equivalent to 9.6 and 19 mg/kg/day respectively) dioxane in drinking water showed no evidence of tumour formation. Only in the highest dose group 1.0% (1055 and 1599 mg/kg/day for males and females respectively) were treatment-related tumours found:
in the liver, carcinomas were found in 10/66 animals surviving at 12 months and cholangiomas in 2/66 animals, while squamous cell carcinomas of the nasal cavities were found in 3/66 animals. - Other effects:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- carcinogenicity
- Effect level:
- 94 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: see 'Remark'
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- carcinogenicity
- Effect level:
- 148 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: see 'Remark'
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- general toxicity
- Effect level:
- 9.6 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- gernal toxicity
- Effect level:
- 16 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- histopathology: non-neoplastic
- Dose descriptor:
- LOEL
- Effect level:
- 9.6 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: equivocal necrosis / inflammation in liver
- Remarks on result:
- other: as re-evaluated by Dourson et al., 2017
- Dose descriptor:
- LOEL
- Effect level:
- 148 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: necrosis / inflammation in the liver
- Remarks on result:
- other: as re-evaluated by Dourson et al., 2017
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 94 mg/kg bw/day (actual dose received)
- System:
- hepatobiliary
- Organ:
- liver
- other: degeneration and necrosis
- Treatment related:
- yes
Data source
Referenceopen allclose all
- Reference Type:
- publication
- Title:
- 1,4-Dioxane. I. Results of a 2-year ingestion study in rats
- Author:
- Kociba R.J., McCollister S.B., Park C., Torkelson T.R. and Gehring P.J.
- Year:
- 1 974
- Bibliographic source:
- Toxicology and applied pharmacology 30: 275-286.
- Reference Type:
- publication
- Title:
- Update: Mode of action (MOA) for liver tumors induced by oral exposure to 1,4-dioxane
- Author:
- Michael L. Dourson, Jeri Higginbotham, Jeff Crum, Heather Burleigh-Flayer, Patricia Nance, Norman D. Forsberg, Mark Lafranconi, John Reichard
- Year:
- 2 017
- Bibliographic source:
- Regulatory Toxicology and Pharmacology 88
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- No specific guideline is mentioned; four groups of rats (60 males and 60 females per group) were maintained on drinking water containing:
0, 0.01, 0.1 and 1.0% dioxane for up to 716 days. - GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- 1,4-dioxane
- EC Number:
- 204-661-8
- EC Name:
- 1,4-dioxane
- Cas Number:
- 123-91-1
- Molecular formula:
- C4H8O2
- IUPAC Name:
- 1,4-dioxane
Constituent 1
- Specific details on test material used for the study:
- - Name of test material: dioxane
- Source: Dow Chemical Co.
- Physical state: colourless liquid
- Storage condition of test material: in amber coloured quart-sized bottles and padded with nitrogen until opened for use.
After opening, dioxane was generally used within one week.
Analysis of various stock samples of dioxane revealed the following:
- Hydrogen peroxide : 10- 340 ppm
- Acetaldehyde : non detectable
- Crotonaldehyd : 220 - 1340 ppm
- 2-Methyl-1,3-dioxolane: 6 - 108 ppm
- Water : 10 - 90 ppm
Acidity: 0.0006 - 0.0042 mequiv./mL
Test animals
- Species:
- rat
- Strain:
- Sherman
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 6-8 weeks
- Diet: ad libitum
- Water: ad libitum
ENVIRONMENTAL CONDITIONS
No data
Administration / exposure
- Route of administration:
- oral: drinking water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Drinking water was prepared by dilution in water (1%; 60 mL dioxane added to 5940 mL water).
The drinking water was prepared twice weekly during the first year, and weekly during the second year.
Periodically samples were taken from storage vessels and individual water dispensers, and analysed for dioxane content by gas chromatography. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Stock samples were analysed for impurities at 6 different times during the 2 years, by gas chromatography.
- Duration of treatment / exposure:
- 716 days
- Frequency of treatment:
- continuous
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0.01 other: %
- Remarks:
- corresponding to 9.6 mg/kg bw/day (males) and 19 mg/kg bw/day (females)
- Dose / conc.:
- 0.1 other: %
- Remarks:
- corresponding to 94 mg/kg bw/day (males) and 148 mg/kg bw/day (females)
- Dose / conc.:
- 1 other: %
- Remarks:
- corresponding to 1015 mg/kg bw/day (males) and 1599 mg/kg bw/day (females)
- No. of animals per sex per dose:
- 60 male and 60 female rats/dose
- Control animals:
- yes, plain diet
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations:
twice weekly (first month)
weekly (month 2-7)
biweekly (afterwards)
WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: daily water consumption was recorded daily during 3 periods:
days 1-113, days 114-198, and days 446-460
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: Yes
- Time schedule for collection of blood: no data
- Anaesthetic used for blood collection: no data
- Animals fasted: no data
- How many animals: no data
- Parameters examined: packed cell volume, total erythrocyte count, Hb, and total and different white blood cell counts.
CLINICAL CHEMISTRY: No data
URINALYSIS: No data
NEUROBEHAVIOURAL EXAMINATION: No data - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, a complete gross pathologic examination was performed.
Organ weights of brain, liver, kidneys, testes, spleen, and heart were recorded.
HISTOPATHOLOGY: Yes
brain
bone and bone marrow
ovaries
pituitary gland
uterus
mesentric lymph nodes
heart
liver
pancreas
spleen
stomach
prostrate
colon
trachea
duodenum
kidneys
esophagus
jejunum
testes
lungs
spinal cord
adrenal gland
parathyroid gland
nasal turbinates
urinary bladder - Statistics:
- Student's T-tets was used for Heamatology parameters, and body and organ weights;
Fisher's Exact probability test was used for analysis of tumors;
Chi-Square contigency tables and Fisher's exact propability was used for survival comparison.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- The concentration of 1% 1,4-dioxane led within two to four months to a severe reduction of survival rates in both sexes, nearly half of the group succumbing after four months. The survival rate after four months was essentially the same for all groups.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Within 2 days after initiating the study the body weights of both sexes at 1.0% 1,4-dioxane were significantly lower than controls. The body weights remained depressed throughout the study.
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No effects on haematology were observed.
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Significantly increased liver weight in rats receiving 1% 1,4-dioxane.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In rats at 0.1 and 1.0% 1,4-dioxane, gross and histopathological examination revealed variable degrees of renal tubular epithelial and hepatocellular degeneration and necrosis, accompanied by regenerative activities in the liver (hepatocellular hyperplastic nodule formation) and renal tubuli. No effects were seen on male and female reproductive organs.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- In rats at 0.1 and 1.0% 1,4-dioxane, gross and histopathological examination revealed variable degrees of renal tubular epithelial and hepatocellular degeneration and necrosis, accompanied by regenerative activities in the liver (hepatocellular hyperplastic nodule formation) and renal tubuli. No effects were seen on male and female reproductive organs.
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Male and female rats receiving 0.1% (equivalent to 94 and 148 mg/kg/day respectively) and 0.01 % (equivalent to 9.6 and 19 mg/kg/day respectively) dioxane in drinking water showed no evidence of tumour formation. Only in the highest dose group 1.0% (1055 and 1599 mg/kg/day for males and females respectively) were treatment-related tumours found:
in the liver, carcinomas were found in 10/66 animals surviving at 12 months and cholangiomas in 2/66 animals, while squamous cell carcinomas of the nasal cavities were found in 3/66 animals. - Other effects:
- no effects observed
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 9.6 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 19 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- histopathology: non-neoplastic
- Key result
- Dose descriptor:
- LOEL
- Effect level:
- 9.6 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: equivocal necrosis / inflammation in liver
- Remarks on result:
- other: as re-evaluated by Dourson et al., 2017
- Key result
- Dose descriptor:
- LOEL
- Effect level:
- 148 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: necrosis / inflammation in the liver
- Remarks on result:
- other: as re-evaluated by Dourson et al., 2017
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 94 mg/kg bw/day (actual dose received)
- System:
- hepatobiliary
- Organ:
- liver
- other: degeneration and necrosis
- Treatment related:
- yes
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.