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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
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP compliant, comparable to guideline study, available as unpublished report, no restrictions, fully adequate for assessment (SIDS score: 1b).
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 992
- Report date:
- 1992
Materials and methods
- Objective of study:
- toxicokinetics
- Principles of method if other than guideline:
- Comparable to guideline study regarding pharmacokinetics and metabolism.
- GLP compliance:
- yes
Test material
- Reference substance name:
- Difluoromethane
- EC Number:
- 200-839-4
- EC Name:
- Difluoromethane
- Cas Number:
- 75-10-5
- Molecular formula:
- CH2F2
- IUPAC Name:
- difluoromethane
- Details on test material:
- Name of test material: difluoromethane
COLD SUBSTANCE:
Source: ICI Chemicals and Polymers
CTL reference number: Y02105/010/001
Purity: 99.94% (checked by GC/MS)
RADIO-LABELLED SUBSTANCE:
Source: Imperial Chemical Industries PLC
CTL reference number: Y02105/012/001
Purity: > 97% (radiochemical purity), >95% (chemical purity, radio GC)
Specific activity: 19 mCi/mmol
Constituent 1
- Radiolabelling:
- yes
- Remarks:
- [14C]-HFC32
Test animals
- Species:
- other: rat and mouse
- Strain:
- other: Alpk:APfSD-1 (rat), Alpk:APfCD-1 (mouse)
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- Rat:
- Strain: Alpk:APfSD Wistar-derived
- Source: Barriered Animal Breeding Unit, ICI Plc (Alderley Park, Cheshire, UK)
- Weight at study initiation: 204-220 g
- Diet: ad libitum
- Water: ad libitum
Mouse:
- Strain: Alpk:APfCD-1
- Source: Barriered Animal Breeding Unit, ICI Plc (Alderley Park, Cheshire, UK)
- Weight at study initiation: 33-34 g
- Diet: ad libitum
- Water: ad libitum
ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 / 12
Administration / exposure
- Route of administration:
- inhalation
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- ADMINISTRATION:
- Type of inhalation study: whole body
- Atmosphere generation: HFC32 was mixed with radio-labeled material using the following procedure to give a specific activity in the range 5.27-7.38 µCi/mmol. The vial containing the radio-labeled material was opened inside an evacuated and sealed 10 litre Tedlar gas bag (SKC, Dorset, UK). The bag was then filled with 5 litres of unlabelled HFC32 followed by 5 litres of silica gel-dried laboratory air. The contents were drawn from the bag and mixed with silica gel-dried laboratory air to give a concentration of 10000 ppm HFC32 which was drawn through the chamber at a flow rate of 1l/min.
- Atmosphere analysis: The atmosphere concentration of HFC32 within the chamber was monitored by gas-chromatography at approximately 20 minute intervals throughout the exposure. During the exposure period samples of the atmosphere (1 ml) were removed every 60 minutes to determine the specific activity of the [14C]-HFC32 within the chamber. - Duration and frequency of treatment / exposure:
- 6 hour(s)
Doses / concentrations
- Remarks:
- Doses / Concentrations:
10000 ppm
- No. of animals per sex per dose / concentration:
- males: 4 rats and 4 mice
- Control animals:
- no
- Details on dosing and sampling:
- EXAMINATION:
- Before exposure:
During the 24h acclimation period, urine was collected over dry ice for fluoride ion determination.
- During exposure:
Urine and faeces were collected over dry ice.
- After exposure:
Urine and faeces were collected over dry ice at 6h-intervals up to 4 days and stored at -20°C.
Expired organic material was collected by dissolution into dry ice cooled acetone (100ml).
Carbon dioxide was collected by dissolution into 2M sodium hydroxide.
Carbon monoxide was collected by passing through a catalyst (Hopcalit, 10g) to convert it to carbon dioxide which was then trapped in 2M sodium hydroxide solution.
Rats:
At termination (4 days), the animals were killed by terminal anaesthesia followed by cervical dislocation (rat 1) or cardiac puncture (rats 2-4). The blood was collected in heparin tubes and part of each blood sample (rats 2-4) was centrifuged at 1500g for 15 minutes at 4°C to obtain plasma. The plasma and whole blood samples were stored at -20°C until analysed for radioactivity and carboxyhaemoglobin. Rat 1 was assayed for total carcass radioactivity. Rats 2-4 were dissected and the following organs and tissues were removed and stored at -20°C until they were assayed for radioactivity: liver, kidneys, lungs, heart, brain, testes, muscle, renal fat, spleen and bone (femur).
Mice:
At termination (4 days), the animals were killed by terminal anaesthesia followed by cervical dislocation (mouse 5) or cardiac puncture (mice 6-8). The blood was collected in heparin tubes and part of each blood sample (mice 6-8) was centrifuged at 1500g for 15 minutes at 4°C to obtain plasma. The plasma and whole blood samples were stored at -20°C until analysed for radioactivity and carboxyhaemoglobin. Mouse 5 was assayed for total carcass radioactivity. Mice 6-8 were dissected and the following organs and tissues were removed and stored at -20°C until they were assayed for radioactivity: liver, kidneys, lungs, heart, brain, testes, muscle, renal fat, spleen and bone (femur).
Every samples were analysed for radioactivity by using:
- a Tri-carb 2000 CD Liquid Scintillation system (Packard Ltd) for urine and expired air
- a Hionic Fluor for carbon dioxide, carbon monoxide, tissues and carcasses
- a Optiphase MP for expired organic material and plasma
- a Packard Sample Oxidiser Model 307 for transforming faeces to radio-labelled carbon dioxide.
Results and discussion
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- Rats:
Absorption was low: approximately 1% of the inhaled dose.
Mice:
Absorption was low: approximately 1 % of the inhaled dose. - Details on distribution in tissues:
- Rats:
The distribution of radioactivity was relatively uniform. The highest concentrations, expressed as nmol of HFC32 per g of tissue, were as follows: lung (286 nmol/g), liver (152 nmol/g), kidney (151 nmol/g), fat (149 nmol/g), spleen (111 nmol/g) and heart (103 nmol/g). Blood and other organs, such as muscle, brain, bone, testes, exhibited concentrations below 100 nmol/g.
Mice:
The distribution of radioactivity was relatively uniform. The highest concentrations, expressed as nmol of HFC32 per g of tissue, were as follows: lung (601 nmol/g), liver (346 nmol/g), kidney (323 nmol/g), spleen (274 nmol/g), fat (235 nmol/g) and heart (221 nmol/g). Blood and other organs, such as muscle, brain, bone, testes, exhibited concentrations below 200 nmol/g.
- Details on excretion:
- Rats:
- Pulmonary elimination:
Radio-labelled organic substance was found in exhaled air (up to 0.5% of the inhaled dose) and reasonably assumed to be unchanged HFC32.
Exhalation of carbon dioxide was the second major route for excretion of HFC32 metabolites and accounted for about 0.23% of the inhaled dose. It is postulated to result from oxydative metabolism mediated by cyt P450.
Carbon monoxide could not be detected as a metabolite in exhaled air. Besides, carboxyhaemoglobin values in treated and control animal were similar (2.5% vs 2.0% respectively). It can be concluded therefore that carbon monoxide, if formed, is an extremely minor metabolite of HFC32.
- Urinary elimination:
Urinary excretion of HFC32 metabolites was found to be the second most favoured route. Those metabolites accounted for 0.13% of the inhaled dose.
- Fecal elimination:
Elimination in faeces was minimal and accounted only for 0.03% of the inhaled dose.
Mice:
- Pulmonary elimination:
. Radio-labelled organic substance was found in exhaled air (up to 0.45% of the inhaled dose) and reasonably assumed to be unchanged HFC32.
. Exhalation of carbon dioxide was the second major route for excretion of HFC32 metabolites and accounted for about 0.27% of the inhaled dose. It is postulated to result from oxydative metabolism mediated by cytochrome P450.
. Carbon monoxide could not be detected as a metabolite in exhaled air. Besides, carboxyhaemoglobin values in treated and control animal were similar (1.3% vs 1.2% respectively). It can be concluded therefore that carbon monoxide, if formed, is an extremely minor metabolite of HFC32.
- Urinary elimination:
Urinary excretion of HFC32 metabolites was found to be the most favoured route. Those metabolites accounted for 0.34% of the inhaled dose.
- Fecal elimination:
Elimination in faeces was minimal and accounted for only 0.07% of the inhaled dose.
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- Rats:
The metabolism of HFC32 was low since metabolites accounted for approximately 0.51% of the inhaled dose.
Carbon dioxide was found to be the main metabolite inasmuch radio-labelled carbon dioxide accounted for 0.23% of the inhaled dose.
Fluoride ions were expected to be released but due to the low metabolism, fluoride levels in urine in exposed rats were similar and even lower than levels observed in unexposed animals (96 vs 114 nmol/h).
The assumed metabolism is described in attached document.
From the known routes of metabolism of dihalomethanes, it is postulated that HFC 32 is biotransformed by oxidation, mediated presumably by cytochrome P450, leading to formic acid (postulated as the major urine metabolite) and then to carbone dioxide.
Mice:
The metabolism of HFC32 was low since metabolites accounted for approximately 0.80% of the inhaled dose.
Carbon dioxide was found to be the main metabolite inasmuch radio-labelled carbon dioxide accounted for 0.27% of the inhaled dose.
The assumed metabolism is the same that presented for rats.
Applicant's summary and conclusion
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