Dichlorodifluoromethane
A written toxicokinetic assessment is presented. The substance displays no toxicological effects in any of the studies proposed, and is deemed to be not harmful for health effects. As such, it is deemed inappropriate in terms of animal welfare to conduct a toxicokinetic assessment when no harmful effects are predicted based on known toxicology. Based on all available data, dichlorodifluoromethane is not anticipated to demonstrate effects following exposure.
Bioaccumulation potential:
Absorption rate - inhalation (%):
Dichlorodifluoromethane is a gaseous substance, of relatively small molecular weight (120.9135). Molecular weights below 500 are favourable for absorption; molecular weights above 1000 do not favour absorption. Its intrinsic properties indicate moderate solubility in water, indicating that it may readily dissolve into the gastrointestinal fluids. In addition, as the molecular weight is low (less than 200) the substance may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. The substance has a relatively low oil/water partition coefficient value (Log Kow = 2.16) indicating that it is theoretically favourable for absorption by passive diffusion.
The relative amounts of CFC-12 absorbed by human beings has been measured (Paulet & Chevrier, 1969; Morgan et al., 1972). Retention was measured using radioisotopically marked chlorofluorocarbons by subtracting the radioactivity exhaled 30 min after inhalation from the amount of radioactivity inhaled with a single breath. In terms of absorption CFC-12 demonstrated a retention of 10.3%. Shargel & Koss (1972) exposed dogs to an equal weight mixture of CFC-11, CFC-12, CFC-113, and CFC-114, and obtained similar results.
Azar et al. (1973) determined the corresponding data for CFC-12 in beagle dogs. After an exposure to 5030 mg/m3 (1000 ppm) for a period of 10 min, 1.1 µg/ml was found in the arterial blood and 0.4 µg/ml in the venous system.
Further absorption and elimination data for CFC-12 atomizer administrations indicated that the degree of preferential absorption may vary among individuals (Dollery et al., 1970; Allen & Hanburys Ltd, 1971; Paterson et al., 1971; Shargel & Koss, 1972). Chlorofluorocarbons were administered to dogs for 5 min at fixed concentrations between 0.3 and 10 vol % in the inspired air. The blood concentrations determined up to 60 min after exposure indicated that CFC-11 is more readily absorbed than CFC-12 or CFC-114 (Clark & Tinston, 1972a).
The results of Adir et al. (1975) and Brugnone et al. (1984) provide additional evidence that CFC-11 is absorbed to a greater extent than CFC-12 in dogs and rabbits. The absorption data correlate well with the liquid/gas partition coefficients for these compounds in whole blood, serum, and olive oil shown in Table 1 below.
Table 1. Partition coefficients of CFC-12
Whole Blooda(human)
Serumc
Olive Oilc
CFC-12
a From: Allen & Hanburys, Ltd (1971).
b From: Chiou & Niazi (1973).
c From: Morgan et al. (1972).
CFC-12 was absorbed 4 times more readily than CFC-114 in a study by Rauws et al. (1973) in which rats were exposed to a mixture of CFC-11, CFC-12, and CFC-114 (weight ratio of 1:2:1). A similar pattern was also seen in monkeys by Taylor et al. (1971) . In each instance, the ratio of CFC-12 to CFC-114 in arterial blood was higher than the ratio of exposure concentrations, indicating that CFC-12 was slightly more readily absorbed than CFC-114.
The available data on chlorofluorocarbon uptake indicate that chlorofluorocarbons can be absorbed across the alveolar membrane, gastro-intestinal tract, the skin, and internal organs. Following inhalation, they are absorbed rapidly by the blood. Blood-tissue absorption is probably the rate-limiting step. After an initial, rapid blood level stabilization, chlorofluorocarbons are still absorbed by body tissues and continue to enter the body.
Allen & Hanburys, Ltd. (1971) found in mice that CFC-12 are taken up by heart, fat, and adrenal tissue after 5-min inhalation exposures. CFC-12 is concentrated from the blood to the greatest extent in the adrenals followed by the fat, then the heart, although the effects are less pronounced than with other chlorofluorocarbons. Paulet et al.(1975) noted that CFC-12 can be distributed to the cerebrospinal fluid of dogs after inhalation exposure.
Metabolic transformation
Of the nine chlorofluorocarbons reviewed by the World Health Organisation, some data regarding metabolism exists for CFC-12.
Published studies on in vivo metabolism exist for CFC-12.
Eddy & Griffith (1971) administered 14C-labelled CFC-12 to rats by the oral route and reported a small amount of metabolism. About 2% of the total dose was exhaled as14CO2and 0.5% was excreted in urine. CFC-12 and/or its metabolites were no longer detectable in the body 30 h after administration.
Blake & Mergner (1974) exposed beagle dogs for 6-20 min to CFC-12 (40 240 to 60 380 mg/m3; 8000 to 12 000 ppm, v/v) containing up to 180 µCi of 14C-chlorofluorocarbon. Virtually all the administered chlorofluorocarbon was recovered in exhaled air within one hour with either material. Only traces of radioactivity were found in urine or exhaled CO2 and may have represented unavoidable radiolabelled impurities rather than metabolites. The authors concluded that less than 1% of CFC-12 is metabolized after inhalation. The preceding results were essentially confirmed in human volunteers by the same authors (Mergner et al., 1975). Radiolabelled CFC-12 (503 mg/m3; 100 ppm) were given by inhalation to one male and one female volunteer for 7-17 min. As was the case in dogs, little or no biotransformation of either chlorofluorocarbon was observed. Total metabolites were equal to, or less than, 0.2% of the administered dose.
The results of the preceding studies suggest that CFC-12 is metabolized to a very small extent, if at all, in mammals following brief inhalation exposures.
Elimination and excretion in expired air, faeces, and urine
Regardless of the route of entry, chlorofluorocarbons appear to be eliminated almost exclusively through the respiratory tract. Little, if any, chlorofluorocarbon or metabolite has ever been reported in urine or faeces (Matsumoto et al., 1963; Blake & Mergner, 1974; Mergner et al., 1975).
Retention and turnover
When exposure is terminated, the more readily absorbed compounds are retained longer. The retention of chlorofluorocarbons after inhalation follows the same order as the amount absorbed during exposure:
CFC-11~CFC-113 > CFC-114~CFC-12
The data of Brugnone et al. (1984) indicate a pulmonary retention of 18% for CFC-12 in workers during occupational exposure.
Studies in which dogs were administered CFC-12 by intravenous infusion indicated that the elimination of CFC-12 from venous blood was triphasic (Niazi & Chiou, 1975, 1977). A 3-compartment model was proposed with initial, intermediate, and terminal half-lives of 1.47, 7.95, and 58.50 min for CFC-12. Adir et al. (1975) also fitted their venous blood elimination data to a 3-compartment model. For CFC-12 elimination, the half-lives were 9.63 min for one human volunteer and 8.45-11.35 Min (mean, 9.90) for three dogs.
Reaction with body components
Lessard & Paulet (1985) concluded that simple dissolution of CFC-12 in the lipid layer of biological membranes with ensuing alteration of membrane configuration may account for its anaesthetic effect and some of its cardiac effects. Young & Parker (1972), however, suggested that CFC-12 is bound to the hydrophilic areas of various phospholipids and that potassium chloride may stop adrenaline-induced arrhythmia in hearts sensitized by CFC-12 by displacing the CFC-12 molecule held by the phospholipid.
Based on all available data, dichlorodifluoromethane is not anticipated to demonstrate effects following exposure. Dichlorodifluoromethane has a very low acute toxicity potential.
The data indicates that should absorption occur following exposure, effects are minimal with some 10% only absorbed. Following this, the substance will be rapidly eliminated in expired air with little actual metabolism. As a result of this, significant bioaccumulation can be excluded, which is supported by calculated QSAR values for bioaccumulation potential.
From the mutagenicity and carcinogenicity assays it appears that Dichlorodifluoromethane is not metabolised towards genotoxic structures. In the event of absorption, significant effects resulting in toxicity are not predicted.