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EC number: 246-791-8 | CAS number: 25291-17-2
- 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:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1 Mar - 24 Aug 2007
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 007
- Report date:
- 2007
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- 2008
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: 28-day Repeated Dose Toxicity Study in Mammalian Species
- Version / remarks:
- prescribed in "Concerning Testing Methods Relating to the New Chemical Substances" [Notification No. 1121002 of the Pharmaceutical and Food Safety Bureau, MHLW, No. 2 (November 13, 2003) ofthe Manufacturing Industries Bureau, METI & No. 031121002 of the Environmental Health Department, MOE (November 21, 2003)].
- Deviations:
- not specified
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-ene
- EC Number:
- 246-791-8
- EC Name:
- 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-ene
- Cas Number:
- 25291-17-2
- Molecular formula:
- C8H3F13
- IUPAC Name:
- 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooct-1-ene
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan Hino Breeding Center, Shiga, Japan
- Age at study initiation: 5 weeks
- Weight at study initiation: 127.3 – 146.1 g (males) and <111.4 – 130.7 g (females)
- Housing: individual in hanging stainless steel cages with wire-mesh floor. Diet and housing material were autoclaved at 121 °C for 30 min prior to use. Undertrays were changed once a week before grouping, and twice a week after grouping. Feeders, cages and racks were changed once at grouping, and once at termination of the dosing period for the recovery group. Racks and cages were identified by individual cards.
- Diet: MF pelleted diet, ad libitum
- Water: chlorinated water, ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.5 - 24.1
- Humidity (%): 47.9 - 58.6
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- olive oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
PREPARATION
The test substance was accurately weighed in an agate mortar and mixed with olive oil (including 1.0% (w/v) Tween 80) to prepare the 2.0% (w/v) formulation under a light shielding condition. The lower concentration formulations of the 0.05 and 0.25% (w/v) were prepared by diluting the 2.0% (w/v) formulation with the vehicle. The formulations were stored at the dark and cold place in the test substance preparation room).
VEHICLE
- Justification for use and choice of vehicle (if other than water): Since the hydrolyzability of the test substance was unknown, olive oil (including 1.0% (w/v) Tween 80) was selected as the appropriate vehicle.
- Concentration in vehicle: 0.05, 0.25 and 2.0% (w/v)
- Amount of vehicle (if gavage): 10 mL/kg
- Lot/batch no. (if required): olive oil (Lot No. 0380HS, Fujimi Pharmaceutical); Tween 80 (Lot No. DPK6694, Wako Pure Chemical Industries) - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- In the homogeneity analysis, top, middle and bottom layers were taken immediately after preparation, and quantitatively analyzed by gas chromatography after sample pretreatment. The homogeneity of the test substance in the formulations was confirmed.
In the stability test, the formulations for homogeneity samples were stored at the dark and cold place. Then, middle layers of the formulations were taken after 9 days, and quantitatively analyzed by gas chromatography after sample pretreatment. The test substance in the formulations was confirmed to be stable for 8 days.
The concentrations of the 2.0, 0.25 and 0.05% (w/v) formulations were confirmed to be within 100 ± 10% of each nominal concentration at the first preparation of the dosing period. - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- once daily, 7 days/week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 5 mg/kg bw/day (nominal)
- Dose / conc.:
- 25 mg/kg bw/day (nominal)
- Dose / conc.:
- 200 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10 (control and high-dose level); 5 (low- and mid-dose level)
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: A 7-day oral range finding study was performed at 0, 25, 250, 500 and 1,000 mg/kg/day in the same testing facility. Enlargement of the liver and increases in liver weight were noted in the groups given 250 mg/kg or more. Accordingly, the high dose was set at 200 mg/kg/day and lower doses of 25 and 5 mg/kg were set for the present study. Recovery groups were also set for the 200 mg/kg and vehicle control groups.
- Rationale for selecting satellite groups: Recovery groups for the high-dose level and conrol group were used to investigate the reversibility of the effects.
- Post-exposure recovery period in satellite groups: 14 d
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: three times a day during treatment period, twice a day during recovery period
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once before dosing, once weekly during dosing and recovery periods
BODY WEIGHT: Yes
- Time schedule for examinations: day 1, 3, 8, 12, 17, 21, 26 and 28
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 28 during the dosing period, day 14 during recovery period
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- Parameters checked: white blood cell count (WBC), differential leucocyte count (neutrophils, lymphocytes, monocytes, eosinophils, basophils, large unstained cells), red blood cell count (RBC), reticulocyte ratio, prothrombin time (PT), activated partial thromboplastin time (APTT), haemoglobin (Hb), haematocrit (Ht), mean corpucular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), platelet count
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day 28 during the dosing period, day 14 during recovery period
- Animals fasted: Yes
- Parameters checked: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), cholinesterase, γ-Glutamyl transpeptidase (γ-GTP), total cholesterol, triglyceride, glucose, total protein, albumin, A/G ratio, blood urea nitrogen, creatinine, total bilirubin, calcium, , inorganic phosphorus, sodium, potassium, chloride
URINALYSIS: Yes
- Time schedule for collection of urine: day 28 during the dosing period, day 14 during the recovery group
- Metabolism cages used for collection of urine: Yes
- Paramters checked: urine volume, color, turbidity, urine specific gravity, pH, protein, glucose, occult blood, urinary sediments - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
- Organs checked: liver, kidneys, adrenal glands, testes, epididymides, thymus, spleen, brain, heart, ovaries
HISTOPATHOLOGY: Yes
- Organs checked: trachea, lung, incisors, stomach, intestine (duodenum to rectum, with Peyer`s patches), liver, heart, kidneys, urinary bladder, testes, epididymides, prostate, seminal vesicles, ovaries, uterus, vagina, brain (cerebrum, cerebellum and pons), spinal cord, sciatic nerve, bone marrow (femur), axillar and mesenteric lymph nodes, spleen, thymus, pituitary gland, thyroid (with parathyroids), adrenals, eye balls - Statistics:
- Data regarding body weights (excluding those at the time of necropsy), food intakes, hematological examinations, blood chemical examinations, urine volume, urine specific gravity, organ weights, grip strength and locomotor activity counts were analyzed by using the Bartlett's test for homogeneity of variance. If the variances were homogeneous at a significance level of 5%, one way analysis of variance was performed. If there was a significant difference in this analysis, the difference between the vehicle control group and each of the treatment group was analyzed by the Dunnett's test. If the variances were not homogeneous, the Kruskal-Wallis's test was used. If there was a significant difference in this analysis, the difference between the vehicle control group and each of the treatment group was analyzed by the nonparametric Dunnett's test.
The frequencies of defecation (number of feces) and urination (number of pools) were analyzed by using the Kruskal-Wallis's test. If there was a significant difference in this analysis, the difference between the vehicle control group and each of the treatment group was analyzed by the nonparametric Dunnett's test.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- MALES
Administration period:
200 mg/kg bw: soft stool (3/10), salivation (9/10)
25 mg/kg bw: salivation (4/5)
5 mg/kg bw: salivation (5/5)
control: salivation (10/10)
Recovery period:
200 mg/kg bw: mottled teeth (2/5)
FEMALES
Administration period:
200 mg/kg bw: salivation (10/10), soft stool (4/10), diarrhea (1/10), loss of hair (forelimb, 1/10)
25 mg/kg bw: salivation (3/5), soft stool (1/5), diarrhea (1/5)
5 mg/kg bw: salivation (1/5), soft stool (1/5), diarrhea (1/5), loss of hair (forelimb, 1/5)
control: salivation (3/10), scab formation (right shoulder, 1/10), loss of hair (forelimb, 1/10), loss of hair (left forelimb, 1/10), loss of hair (right shoulder, 1/10)
Recovery period:
200 mg/kg bw: loss of hair (forelimb, 1/10)
control: loss of hair (forelimb, 1/10)
Salivation was considered to be a physiological response rather than a sign of systemic toxicity as it was observed after dosing and no change related to the neural system was observed in the histopathological examinations, detailed clinical observations of the sensorimotor function. Soft stool or diarrhea were single occurrence. As no histopathological change was observed, these effects were considered to be incidental. Loss of the hair in the forelimbs occurred only in one animal each of the control group, low- and high-dose group and was therefore not considered to be treatment-related.
The summary of clinical signs is shown in Table 1 under "any further information on results incl. tables". - Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- FEMALES
5 mg/kg bw/day: significant increase in WBC compared with the control group, since this increase was not observed in the mid- and high-dose group it was not considered to be treatment-related.
MALES
200 mg/kg bw/day recovery group: significant increase of neutrophils and significant decrease of lymphocytes and large unstained cells was noted compared with the recovery control group. This effect was not noted in the other male high-dose group therefore the effect was not considered to be treatment-related. - Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- MALES
200 mg/kg/day: Significant increase in absolute (30%) and relative (36%) liver weight, significant decrease in absolute heart weight (12%), and absolute (31%) and relative (27%) spleen weights were observed compared with the control group.
200 mg/kg/day recovery: Relative kidney weight (10%) and absolute weight of epididymis (10%) were significantly increased compared with the recovery control group.
25 mg/kg bw/day: Significant increased relative liver weight (13%) compared with the control group was determined.
FEMALES
200 mg/kg bw/day: Relative (8%) kidney weight and relative (15%) liver weight were significantly increased compared with the control group.
25 mg/kg bw/day: Absolute (21%) and relative (14%) liver weights were significantly increased compared with the control group.
The increases of absolute and relative liver weights in the mid- and high-dose groups, respectively, were considered to be treatment-related with toxicological relevance, as these effects occurred in both sexes and were dose-dependent. Furthermore, changes in liver, such as centrilobular lipid droplets in hepatocytes and microgranuloma, were observed in the male high-dose group, in the male high-dose recovery group and occasionally in the female mid- and high-dose group after histopathological examination, please refer to "Histopathological findings, non-neoplastic". In addition to the influence on liver weights and the changes observed after histopathological examination, an enlargement of the liver in all high-dose males compared with the control group was noted after magroscopic examination, please refer to "Gross pathological findings".
The summary of absolute and relative organ weights is shown in Table 2 under "any further information on results incl. tables". - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- MALES
At termination of dosing period:
200 mg/kg bw/day: enlargment of the liver (5/5)
25 mg/kg bw/day: cyst of the pituitary gland (1/5)
5 mg/kg bw/day: whitish region on the capsule of the spleen (1/5)
control: sparsed fur on the skin (1/5)
At termination of recovery period:
200 mg/kg bw/day: mottled teeth (3/5)
FEMALES
At termination of dosing period:
200 mg/kg bw/day: elevated region of the mucosa in the forestomach (1/5)
control: scab formation of the skin (1/5)
At termination of recovery period:
200 mg/kg bw/day: mottled teeth (1/5), loss of hair (forelimb, 1/5)
control: loss of hair (forelimb, 1/5) - Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- MALES
At termination of dosing period:
200 mg/kg bw/day: centrilobular lipid droplets in the hepatocytes of the liver (3/5 slight and 2/5 moderate), slight periportal hypertrophy of the hepatocytes of the liver (1/5), slight periportal prominent nucleoli of the hepatocytes of the liver (1/5), slight microgranuloma of the liver (4/5), slight degeneration of the spermatocytes of the testis (1/5), slight germ cell debris in the lumen of the epididymis (1/5)
25 mg/kg bw/day: slight centrilobular lipid droplets in the hepatocytes of the liver (1/5), moderate microgranuloma of the liver (1/5), moderate cyst formation in the pars intermedia of the pituitary gland (1/5)
5 mg/kg bw/day: slight capsultitis of the spleen (1/5)
control: slight focal necrosis in the Peyer`s patches of the jejunum (1/5)
At termination of recovery period:
200 mg/kg bw/day: centrilobular lipid droplets in the hepatocytes of the liver (3/5 slight and 1/5 moderate), slight microgranuloma of the liver (3/5)
control: slight mineralization in the medulla of the kidneys (1/5), moderate inhibited spermiation and deep retention of the spermatids of the testis (1/5)
FEMALES
At termination of dosing period:
200 mg/kg bw/day: slight centrilobular lipid droplets in the hepatocytes of the liver (1/5), slight microgranuloma of the liver (2/5), slight lymphocyte infiltration in the submucosal layer of the forestomach (1/5), slight edema in the submucosal layer of the glandular stomach (1/5), slight mineralization in the cortico-medullary junction of the kidney (1/5)
25 mg/kg bw/day: slight peliportal lipid droplets in the hepatocytes of the liver (1/5), slight microgranuloma of the liver (1/5)
control: slight focal inflammation of the rectum (1/5), slight ulcer of the skin (1/5), slight microgranuloma of the liver (1/5)
At termination of recovery period:
control: slight microgranuloma of the liver (1/5) - Histopathological findings: neoplastic:
- no effects observed
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 5 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: no adverse effects observed at the lowest dose level
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 25 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- gross pathology
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 5 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Any other information on results incl. tables
Table 1 Summary of clinical signs
Signs | Dosing Period | Recovery Period | ||||||
VC | VC (Recovery) | 5 mg/kg bw/d | 25 mg/kg bw/d | 200 mg/kg bw/d | 200 mg/kg bw/d (Recovery) | VC | 200 mg/kg bw/d | |
MALE | 5 animals / group | |||||||
No abnormalities detected | 2 | 1 | 1 | 5 | 3 | |||
Salivation | 5 | 3 | 5 | 4 | 5 | 4 | ||
Soft stool | 2 | 1 | ||||||
Mottled teeth | 2 | |||||||
Loss of hair (ventral neck) | ||||||||
FEMALE | 5 animals / group | |||||||
No abnormalities detected | 1 | 4 | 2 | 2 | 4 | 4 | ||
Salivation | 3 | 1 | 3 | 5 | 5 | |||
Soft stool | 1 | 1 | 2 | 2 | ||||
Diarrhea | 1 | 1 | 1 | |||||
Loss of hair (right shoulder) | 1 | |||||||
Loss of hair (forelimb) | 1 | 1 | 1 | 1 | ||||
Loss of hair (left forelimb) | 1 | |||||||
Loss of hair (right shoulder) | 1 |
VC = Vehicle control
Table 2 Summary of absolute (g) and relative (g/100g)) organ weights in males
Exp. Group [mg/kg/day] | Number of animals | Liver (g) | Liver (g/100g) | Heart (g) | Spleen (g) | Spleen (g/100g) |
VC | 5 | 10.07 ± 1.02 | 3.09 ± 0.24 | 1.14 ± 0.10 | 0.70 ± 0.14 | 0.22 ± 0.05 |
5 | 5 | 11.08 ± 1.51 | 3.26 ± 0.12 | 1.16 ± 0.05 | 0.60 ± 0.07 | 0.18 ± 0.02 |
25 | 5 | 11.39 ± 1.69 | 3.50 ** ± 0.19 | 1.08 ± 0.10 | 0.58 ± 0.06 | 0.18 ± 0.02 |
200 | 5 | 13.03 ** ± 1.08 | 4.22 ** ± 0.13 | 1.00 * ± 0.07 | 0.48 ** ± 0.07 | 0.16 * ± 0.02 |
VC (Recovery) | 5 | 10.85 ± 2.73 | 2.83 ± 0.34 | 1.23 ± 0.16 | 0.65 ± 0.12 | 0.17 ± 0.01 |
200 (Recovery) | 5 | 11.17 ± 1.07 | 3.00 ± 0.15 | 1.24 ± 0.12 | 0.56 ± 0.04 | 0.15 ± 0.02 |
VC = Vehicle control
* Significantyl different from vehicle control at P<0.05.
** Significantyl different from vehicle control at P<0.01.
Applicant's summary and conclusion
- Conclusions:
- Based on the effects on the increased liver weights, the enlarged liver size and histopathological findings in the liver at 25 mg/kg bw/day, the substance is classified as STOT-RE 1, H372, oral, liver.
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