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EC number: 200-839-4 | CAS number: 75-10-5
- 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
The NOAEL for repeated dose toxicity is higher than about 105000 mg/m3 (50000 ppm v/v) in rats (highest tested concentration) exposed for a period of 90 days.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
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:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP compliant, near-guideline study, available as unpublished report, no restrictions, fully adequate for assessment (SIDS score: 1b).
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Alpk:APfSD (Wistar-derived)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ORGANISMS:
- Source: Alderley Park (Cheshire, UK)
- Age at stuyd initiation: 5-6 weeks
- Mean body weight at study initiation: 141-169 g for males, 130-151 g for females
- Satellite groups: 10 additional males and 10 additional females were included with high and control groups in order to study reversibility for 4 weeks after the end of exposure.
- Housing: 5 per cage (sexes seperately)
- Diet: ad libitum
- Water: ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-20
- Humidity (%): 35-65
- Photoperiod (hrs dark / hrs light): 12 / 12 - Route of administration:
- inhalation
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: unchanged (no vehicle)
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure generation: atmosphere generation: test atmospheres were generated by passing liquid HFC 32 through a copper coil immersed in a water bath maintained at 45°C. The resultant vapour was then passed through an equilibration coil to flowmeters via a copper distribution plenum.
- Expsure chamber volume: 300 l
- Air flow rate: 70 l/min
TEST ATMOSPHERE
- Brief description of analytical method used: test atmospheres were sampled using an automated air sampling system and analysed automatically using a gas chromatograph (Hewlett Packard HP5880A) including a Porapak P-S column (80/100 mesh, 1.8m x 4mm ID stainless steel, Waters Ltd.), fitted with a gas sampling valve (Hewlett Packard) and a flame ionisation detector. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Test atmospheres were sampled using an automated air sampling system and analysed automatically using a gas chromatograph (Hewlett Packard HP5880A) including a Porapak P-S column (80/100 mesh, 1.8m x 4mm ID stainless steel, Waters Ltd.), fitted with a gas sampling valve (Hewlett Packard) and a flame ionisation detector. The peak area attributable to HFC 32 was used to calculate the atmosphere concentration in parts-permillion (ppm v/v), after suitable calibration (Hewlett Packard HP3396A integrator, Waters 860 Networked Vax Data System).
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- 6 hours/day, 5 days/week
- Remarks:
- Doses / Concentrations:
5000, 15000, 50000 ppm (v/v)
Basis:
nominal conc. - Remarks:
- Doses / Concentrations:
4940 ± 160, 14600 ± 470 and 49100 ± 1600 ppm (v/v)
Basis:
analytical conc. - No. of animals per sex per dose:
- 10 males and 10 females per dose group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Post-exposure period: 4 weeks (only for control and high-dose groups)
- Observations and examinations performed and frequency:
- CLINICAL OBSERVATIONS AND FREQUENCY:
- Clinical signs: observed frequently during exposure and then once a day
- Mortality: daily noted
- Body weight: recorded every weeks (on the same day)
- Food consumption: weekly measured - Sacrifice and pathology:
- ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Weighted organs: adrenals, brain, heart, kidneys, liver, lungs (with trachea attached but larynx removed), spleen and testes.
- Macroscopic and microscopic examination: Cardio-vascular and hematopoietic system: heart, aorta, lymph node (mesenteric), thymus, spleen, bone marrow . Digestive system: oral cavity, salivary glands, oesophagus, stomach, liver, pancreas, duodenum, jejunum, ileum, caecum, colon, rectum. Glandular system: pituitary, thyroid, parathyroids, adrenal, mammary gland, Harderian gland. Nervous system: brain, spinal cord, sciatic nerve, eye. Respiratory system: nasal turbinates, trachea, lungs, larynx. Uro-genital system: kidney, bladder, ovary, uterus, testes, epididymides, seminal vesicle, prostate, cervix. Other: skin, muscles, femur, sternum. - Other examinations:
- - Haematology: blood samples were taken by tail bleeding from 5 males and 5 females on week 5 and 14 (every main study groups) and on weeks 18 (satellite groups).
Parameters measured by a using a Technicon H1 analyser (Bayer Diagnostics): haemoglobin, haematocrit, red blood cell count, white blood cell count, differential leukocyte count (only for control and high-dose groups), platelet count, mean cell volume, mean cell haemoglobin concentration, mean cell haemoglobin
Parameters measured on a "Coag-a-mate" (Organon-Teknika): prothrombin time, kaolin-cephalin time.
- Blood chemistry: blood samples were taken by tail bleeding from 5 males and 5 females on week 5 and 14 (every main study groups) and on weeks 18 (satellite groups). The following parameters were measured by using a Kone specific analyzer:
Electrolytes: calcium, chloride, phosphorous (as phosphate), potassium, sodium
Enzymes: alkaline phosphatase, alanine-aminotransferase, aspartate-aminotransferase, gamma-glutamyl-transferase, creatinine kinase
Other: albumin, blood creatinine, blood urea nitrogen, glucose, total bilirubin, total cholesterol, total serum protein, triglycerides
- Urinanalysis: urine samples were collected overnight on the last day of weeks 4 and 12 from 5 males and 5 females from each main study group and on the last day of weeks 13 and 16 from 5 males and 5 females per satellite group.
Parameters measured with a Jenway 3040 Ion Analyser: colour, urine volume and pH
Parameter measured with an ATAGO refractometer: specific gravity
Parameters measured with ames Multistix SG strips (Bayer Diagnostics): proteins, glucose, ketones, blood, urobilinogen
Parameter measured with a Russell Ion Selective Electrode in conjunction with the Jenway 3040 Ion Analyser: fluoride. - Statistics:
- Bodyweights were considered by analysis of covariance and food consumption by analysis of variance on initial bodyweight, separately for males and females.
Haematology, blood and urine clinical chemistry were considered by analysis of variance. With the exception of urine protein, male and female data were analysed together and the results examined to determine whether any differences between control and treated groups were consistent between sexes.
Organ weights were considered by analysis of variance and analysis of covariance on final bodyweight, separately for males and females. Differences from control were tested statistically by comparing each treatment group least-squares mean with control group least-squares mean using a two-sided Student's T-test, based on the error mean square of the analysis. - Clinical signs:
- no effects observed
- 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 specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS: There were no clinical abnormalities observed during exposure and none observed during the study which were attributable to exposure to HFC 32. Those findings recorded during the study were few in number and were of a type and incidence normally expected in rats of this age and strain (chromodacryorrhea, damaged tails, trimmed teeth, one upper incisor missing).
MORTALITY: No deaths occurred during the study.
BODY WEIGHT: There were no effects of exposure to HFC 32 on male or female body weights. Minor differences in bodyweight, some of which achieved statistical significance, were seen but these were small (from -2.7% to +3.76% when compared to control) and showed no coherent dose response relationship.
FOOD CONSUMPTION: There were no effects of exposure to HFC 32 on male or female food consumption. Some variation between the groups/times was seen but this is expected in studies where there are only 2 cages/sex/group, resulting in mean levels that are highly sensitive to any unusual values. A number of statistically significant differences were seen sporadically between treatment groups and control. However, the authors consider them as small (from -16.4% on week 12 in females exposed to 49100 ppm to +10.3% on week 11 in males exposed to 49100 ppm) and possibly attributed to the factors described above. Furthermore, the lack of dose-relationship make them of no toxicological relevance.
OPHTHALMOSCOPY: A small incidence of ocular changes (stained eyelid, hazy corneal opacity, increased lacrymation) was observed in treated and control animals. None was considered to be treatment related and the nature and incidence of these changes were consistent with expected background for this strain of rat.
HAEMATOLOGY: There were no effects of exposure to HFC 32 on male or female haematology parameters. Tere was an increase of platelet count in all treated males on week 5 (+41.0% at 4940 ppm, +45.4% at 14600 ppm and +38.8% at 49100 ppm). This difference was considered attributable to individual control values which were more variable than expected, was not evident at week 14 and is therefore conidered unrelated to treatment. The other occasional statistically significant changes were small, did not follow a coherent dose or time relationship and consequently are not considered to be related to treatment. They consist in:
- a decrease in mean cell haemoglobin concentration (-1.8%) in exposed males and a slight increase in monocyte count in females from the satellite group, both groups exposed to 49100-ppm on week 14,
- a decrease in white blood cell count (-13.1%) and lymphocyte count (-16.6%) on week 18 in males from the satellite group exposed to 49100 ppm, - a decrease in red blood cell count (-3.5%) and an increase in mean cell haemoglobin (+2.8%) on week 18 in females from the satellite group exposed to 49100 ppm.
BLOOD CHEMISTRY: There were no effects of exposure to HFC 32 on male or female blood chemistry parameters. Statistically significant differences were found in some parameters:
- a decrease in creatinine in males on week 5 (-30.3% at 14600 ppm and -24.2% at 49100 ppm) and on week 14 (-14.8% at 4940 ppm and -19.7% at 49100 ppm), and in females on week 14 too (-15.5% at both 4940 ppm and 14600 ppm),
- an increase in triglycerides in males on week 5 (+48.7% at 49100 ppm) and on week 14 (+32.2% at 49100 ppm) but a decrease in females on week 14 (-26.8% at 4940 ppm),
- a decrease in bilirubin in females on week 14 (-37.8%, -35.1% and- 32.4% at 4940 ppm, 14600 ppm and 49100 ppm respectively). All of these differences are considered attributable to high individual control values (with the exception of triglycerides in males at 49100 ppm which is attributable to high individual values in this group), showed no coherent dose/time relationship and are considered to be unrelated to treatment.
Other statistically significant differences consist in:
- an apparent increase in alanine-aminotransferase (ALAT) in males on week 5 (+23.3% at 4940 ppm) ; a dose-related increase in ALAT in females on the same week (+26.0%, +30.7% and +34.4% at 4940 ppm, 14600 ppm and 49100 ppm respectively).
- an increase in aspartate-aminotransferase (ASAT) in females on week 14 (+25.3% at 4940 ppm),
- a decrease in gamma-glutamyl-transferase in females on week 14 (-52.0% at 4940 ppm),
- an increase in alkaline phosphatase in females on week 14 (+28.0% at 49100 ppm),
- a decrease in cholesterol in males on week 5 (-14.2% and -22.3% at 4940 ppm and 14600 ppm, respectively),
- a decrease in glucose in females on week 5 (-10.8% at 14600 ppm),
- an increase in calcium in males on week 14 (+5.6% at 14600 ppm),
- a decrease in phosphorus in the male satellite group on week 18 (-7.1%).
However, these differences were small, and/or attributable to high individual values, showed no relationship with dose/time and were considered to be unrelated to treatment.
URINALYSIS: There were no effects of exposure to HFC 32 on male or female urinalysis. There was an apparent dose related increase in urine volumes in both sexes at week 5 (in males +38.2% and statistically significant at 49100 ppm only when compared to controls ; in females +73.3% and statistically significant only at 14600 ppm) with a concommittant reduction in specific gravity. These differences were not evidenced at week 13 and considered to be of no toxicological significance. Other occasional statistically significant changes showed no consistent relationship to exposure concentration or time and are considered to be unrelated to treatment. They consist in:
- a decrease in proteinuria on week 5 in females at 4940 ppm (-50.7%) and on week 17 in the satellite male group exposed to 49100 ppm (-20.2%),
- a decrease in fluoride in males at 4940 ppm on weeks 5 and 13 (-22.5% and -27.3% respectively) but an increase in females on week 5 at 14600 ppm and 49100 ppm (+34.8% and +54.5% respectively),
- a small decrease in pH in males and/or females occasionally on week 5, 13 or 17.
NECROPSY:
- Organ weight: There were no effects of exposure to HFC 32 on male or female organ weight.
There was a statistically significant decrease in relative kidney weight in all treated female groups at week 14 (-6.1% in all groups). This change was small and consistent accross all groups, showed no relationship to exposure concentration and considered not to be related to exposure. In addition, there was a statistically significant increase in relative liver weight in males at week 14 (+8.6% at 4940 ppm, +9.2% at 49100 ppm). These diferences were small, showed no coherent dose relationship, did not correlate with any clinical chemistry or histopathological changes and are considered to be unrelated to treatment.
- Macroscopic findings: There were no gross findings which were considered to be treatment related.
- Microscopic findings: At termination of the study in week 14, there was a slight increase over controls of unilateral hydronephrosis in the kidneys of male rats exposed to 49100 ppm (5 cases vs 1 in control). The incidence of this finding in male control rats from the satellite group (30%) was higher than in male controls at 14 weeks (10%) and similar to the incidence in males exposed to 49100 ppm terminated after 14 weeks (50%). This was, therefore, considered to be an incidental finding. Other changes were either present to the same extent in controls or were considered to be part of the normal spectrum of changes seen in this strain of rat. - Dose descriptor:
- NOAEL
- Effect level:
- 49 100 ppm
- Sex:
- male/female
- Basis for effect level:
- other: no toxic effects observed
- Critical effects observed:
- not specified
- Conclusions:
- Inhalation exposure of rats to measured concentrations of 0, 4940, 14600 and 49100 ppm (v/v) HFC 32 (6 hours/day, 5 days/week) for 13 weeks produced no effects considered attributable to exposure to HFC 32.
- Executive summary:
Groups of 10 male and 10 female Alpk:APfSD (Wistar-derived) rats were exposed to nominal values of 0, 5,000, 15,000 and 50,000 ppm (0, 10.5,31.5 and 105 g/m3) HFC-32 (6 hrs/day, 5 days/week). Additional groups of 10 male and 10 female rats were designated for a 4-week recovery period. The highest exposure concentration tested (50000 ppm) is considered to be a limit concentration for studies of this type on low toxicity, highly volatile fluorocarbons. No deaths, no treatment-related effects on clinical signs, bodyweights, food consumption, haematological and clinical chemistry parameters, and urine analyses were observed during the treatment and treatment-free periods. There were no changes attributable to HFC 32 exposure on group mean organ weights (including testes) or in the incidence of macroscopic or microscopic pathology findings (including reproductive organs) in any exposed group. Therefore, the NOAEC in rats was considered to be 50000 ppm v/v (105 g/m3).
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 105 000 mg/m³
- Study duration:
- subchronic
- Experimental exposure time per week (hours/week):
- 30
- Species:
- rat
- Quality of whole database:
- The study was assessed for its reliability and was concluded to be reliable without restrictions.
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
In accordance with section 2 of REACH Annex XI, studies via the oral and dermal route do not need to be conducted as the substance is a gas.
Regarding inhalation exposure, the most reliable data are provided from a 28-day and a 13-week inhalation studies in Alpk:ApfSD (Wistar-derived) rats (GLP, near-guideline studies).
Animals were whole body exposed 6 hours/day, 5 days/week to HFC 32 up to nominal concentration of 50000 ppm v/v (105000 mg/m3) for 28 days or 13 weeks respectively. The highest exposure concentration tested (50000 ppm, 105000 mg/m3) is considered to be a limit concentration for studies of this type on low toxicity, highly volatile fluorocarbons. In both studies, there were no deaths, no treatment-related effects on clinical signs, bodyweights, food consumption, haematological and clinical chemistry parameters, and urine analyses. There were no changes attributable to HFC 32 exposure on group mean organ weights (including testes) or in the incidence of macroscopic or microscopic pathology findings (including reproductive organs) in any exposed group. Therefore, the NOAEC in rats is 50000 ppm v/v (105000 mg/m3) based on the 13 week study.
Justification for classification or non-classification
Based on the NOAEL of 105000 mg/m3 in a 13 week subchronic toxicity study with rats, classification of difluoromethane for repeated dose toxicity is not warranted according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2000.
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