Toxicological Profile of HFA 227

HFA 227 is a colourless gas with an ethereal odor at ambient temperature. If has a very low acute toxicity. No deaths occurred when rats and mice were exposed by inhalation once to 300,000 and 500,000 ppm respectively. Signs of narcosis were observed from 100,000 ppm.

HFA 227 released into the eyes of rabbits did not induce any sign of irritation. Long term exposure of the airways of different test species (rats, dogs) at experimentally high concentrations of HFA 227 caused no irritation nor any untoward effect on the integrity of the respiratory tract function.

HFA 227 can induce cardiac sensitisation in dogs at concentrations from 100,000 ppm 10% v/v) and higher after an exogenous epinephrine challenge.

In long term studies in which rats and dogs were exposed via inhalation to HFA 227 at concentrations up to 240,000 ppm (1 hour per day for 6 months), no treatment related effects of toxicological significance were observed.

In several fertility studies in male and female rats in which animals were exposed for 1 to 6 hours per day to HFA 227 concentrations up to 150,000 ppm, no effects of toxicological significance were observed when measured on the fertility and pregnancy index. Concentrations of up to 150,000 ppm HFA 227 had no embryotoxic nor fetotoxic effects in rats or rabbits. Similar concentrations had no significant effect on the development and behaviour of the offspring of exposed rats.

Different in vitro and in vivo mutagenicity tests were performed with HFA 227. No geneotoxic potential was observed. The in vitro chromosomal aberration test performed on human lymphocytes showed effects that were considered to be related to oxygen deprivation in the test system.

When rats and mice were exposed by inhalation to concentrations of 0, 60,000, 120,000 and 240,000 ppm for 2 years at a regimen of 1 hour per day, no increased incidence of benign or malign neoplasms were observed when compared to controls.

Some alveolar histiocytosis was observed in the lungs of rats exposed to high doses of HFA 227. In view of its normal incidence in this strain of animals and its only very slightly increased severity compared to controls, this effect was considered of no biological significance.

In human volunteers exposed to concentrations up to 8,000 ppm for one hour, no treatment related effects on cardiac performance, pulse rate, blood pressure and lung function were observed when compared to air control and CFC-12 reference conditions.

Pharmacokinetic parameters indicated that blood levels of HFA 227 increased in an exposure related pattern. In males, blood levels were higher than in females.

HFA 227 showed a biphasic elimination from the body after exposure. (mean T1/2: approx. 6.5 minutes and 44.5 minutes). These values appeared to be independent of the exposure concentration.

Acute toxicity to aquatic organisms is very low (LC₀ fish = or > 30 mg/l; EC₀ bacterial activity = or > 173 mg/l). Although no significant biodegradation has been observed, the high volatility and low bio-accumulation potency makes any impact of heptafluoropropane on the aquatic environment highly unlikely.

* LC50, lethal concentration for 50 % of the population of rats, 4h exposure
** LOAEL: Lowest Observable Adverse Effect Level

Toxicological Profile of HFA 134a

HFA 134a is a non-flammable, colourless gas with a faint ethereal odor.

HFA 134a has a very low order of acute toxicity. Concentrations over 700,000 ppm in inhaled air are required to produce lethal effects. The symptoms of acute intoxication are characterised by central nervous system effects due to narcotic properties seen only at extremely high exposure concentrations.

When HFA 134a is in contact with cutaneous or ocular mucosal membranes it causes slight irritation possibly due to evaporation. It does not sensitise the skin.

HFA 134a can induce cardiac sensitisation in dogs at levels of 80,000 ppm (8% v/v) and higher following exogenous epinephrine challenge.

The chronic toxicity of HFA 134a was studied in rats at inhalation exposure levels up to 50,000 ppm. No significant toxicological effects were observed in these studies.

HFA 134a showed no adverse effects on fertility in mice. It was not teratogenic in rats or rabbits. Only non-specific effects on fetal maturation, in the form of delayed fetal ossification in rats were observed at 50,000 ppm and above.

HFA 134a was not genotoxic in vitro or in vivo as shown in a large variety of studies, including all important end points.

In a limited study in rats involving daily oral administration of 300 mg/kg body weight HFA 134a dissolved in corn oil over a period of 1 year, and a 16 month post-treatment observation phase, no tumorigenic effects were seen.

In a two year inhalation study with exposures up to 50,000 ppm, HFA 134a only produced some benign changes in the testes of rats exposed to the highest concentrations. These changes are considered of limited relevance to humans.

In human volunteers exposed to concentrations up to 8,000 ppm for one hour, no treatment related effects on cardiac performance, pulse rate, blood pressure and lung function were observed when compared to air control and CFC-12 reference conditions.

Pharmacokinetic parameters indicated that blood levels of HFA 134a increased in an exposure related pattern. In males, blood levels were higher than in females. HFA 134a showed biphasic elimination from the body after the end of exposure. (T1/2: approx. 10 minutes and 43 minutes). These values appeared to be independent of the exposure concentration.

Acute toxicity to aquatic organisms is very low. Although no significant biodegradation has been observed, the high volatility and low bio-accumulation potency makes any impact on the aquatic environment highly unlikely.

* LC50, lethal concentration for 50 % of the population of rats, 4h exposure
** LOAEL: Lowest Observable Adverse Effect Level

Safety Instructions

Solkane® 227 pharma and Solkane® 134a pharma are liquefied compressed gases.

According to pressure vessel regulations, compressed gases are substances whose vapour pressure at 50 °C is above 3 bar. In line with the regulations governing pressure vessels, these may only be transferred to approved and labelled gas-tight gas cylinders or containers.

Recommended Safety Procedure

HFA 227 and HFA 134a are non-flammable gases. But, wherever they are handled, there must be no open flames or heat sources (e.g. hot metallic surfaces) or reactive products. The propellants can decompose and the decomposition products are corrosive, irritate the mucous membranes and are poisonous when inhaled.

The decomposition compound, hydrogen fluoride, is highly toxic. However, it is easily recognised by its odor. Even small amounts, below the danger limit for humans, are noticeable in the ambient air. Also, the decomposition product vapours should be prevented from contacting hot spots and electric arcs (welding). Containers that have been exposed to fire should not be approached until sufficiently cooled (e.g. by large quantities of water).

HFA 227 and HFA 134a should only be used with the equipment and materials which are compatible with the products. Contact with alkaline and alkaline-earth metals may provoke violent reactions or explosions.

Storage and work areas must be well ventilated. In particular, ventilation must be effective at ground level because the propellant vapour is heavier than air and displaces available oxygen.

Recommended Working Conditions

When inhaled at high concentrations (for inhalation limits see page 30/31), there is a danger of narcosis, cardiac arrhythmia or asphyxia through lack of oxygen. Therefore, all products should be handled in a ventilated, cool area. An important precondition is strict adherence to the threshold limit value (TLV).

Respiratory Protection:

• Minimal need if the local exhaust ventilation is adequate
• Self-contained breathing apparatus should be used when insufficient oxygen is present (large uncontrolled emissions) and in all circumstances when the mask and cartridge do not give adequate protection
• Use only respiratory protection that conforms to international and/or national standards

HFA 227 and HFA 134a as vapours have little or no effect on the skin or eyes. To avoid the cold irritation and frostbite from exposure to the liquid propellants, certain precautions have to be followed during handling. Skin frequently exposed to the propellant can become dry and chapped and there is a risk of developing chronic dermatitis.

Severe eye irritation, watering, redness and swelling of the eyelids, burns (frostbite) can occur as a result of contact with liquefied propellant.

Flammability

HFA 227 and HFA 134a are non-flammable gases and do not form explosive mixtures with air at any mixing ratio under ambient temperature and atmospheric pressure. However, all propellants containing hydrogen may form explosive mixtures with air under certain conditions.

HFA 134a vapour may form explosive mixtures with air under increased pressure. At atmospheric pressure, an HFA 134a pharma vapour/air mixture is not explosive at temperatures below 280 °C^[33]. The pressure limit for the formation of explosive mixtures in air is dependent on the temperature.

During leak detection or pressure testing, compressed gas must never be used with propellants which contain hydrogen.

Solkane® 227 pharma and Solkane® 134a pharma

• Hazardous Decomposition Products:
  Hydrogen fluoride, fluorophosgene (HFA 227), carbon monoxide (HFA 134a)
• Packaging Material:
  Ordinary steel, aluminium
• Flammability Limits in Air at Normal Conditions:
  None

Skin Protection:

• Handle only with impervious apron/boots if there is a risk of splashing
• Gloves, overalls and boots should be double layered (protection against cold)

Hand Protection:

• Protective gloves (recommended material for HFA 227 and HFA 134a is polyvinylalcohol)

Eye Protection:

• Wear protective goggles for all industrial operations
• If risk of splashing: chemical-proof goggles/face shield are required