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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

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:
1974
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:
2017
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

Constituent 1
Chemical structure
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
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